Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases Qi-Wei Jiang,1 ∗ Mei-Wan Chen,2 ∗ Ke-Jun Cheng,3 ∗ Pei-Zhong Yu,4 Xing Wei,1 and Zhi Shi1 1 Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, Guangdong, China 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 519000, China 3 Chemical Biology Center, Lishui Institute of Agricultural Sciences, Lishui 323000, Zhejiang, China 4 Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 200433, China

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21346

䉲 Abstract: Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their  C 2015 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 0, 1–25, efficacy and safety in cancer and other diseases. 2015

Key words: steroidal alkaloids; bioactivities; anticancer effects; apoptosis

1. INTRODUCTION Natural products have been playing a critical role in the prevention and treatment of cancer and other disease around the world. Their ethnopharmacological properties have not only provided useful tools for the study of major pharmacological properties, but also led to discovering a number of drugs.1–3 As one large family of natural products, alkaloids are well known for their diverse pharmacological properties and are mainly found in various parts of plant ∗ These

authors contributed equally to this work.

Correspondence to: Zhi Shi, Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China, E-mail: [email protected]. Medicinal Research Reviews, 00, No. 0, 1–25, 2015  C 2015 Wiley Periodicals, Inc.

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Figure 1.

The main natural sources of steroidal alkaloids.

including seeds, roots, stems, flowers, leaves, and fruits. Currently, alkaloids and their analogues almost account for half of clinical drugs, especially anticancer drugs, where vinca alkaloids, camptothecin analogues, and paclitaxel derivatives are widely used to treat multiple types of cancers.4, 5 Steroidal alkaloids are an important class of alkaloids and secondary metabolites that occur in plants including Solanaceae, Apocynaceae, Liliaceae, and Buxaceae, amphibians and marine invertebrates, and are generally isolated in the glycoalkaloids form (Fig. 1). 6–8 For example, the total steroidal alkaloid level is estimated to be 123–7348 mg/kg of fresh weight in tubers and leaves of Solanum species used in potato breeding.9 Steroidal alkaloids and their glycosides are reported to have varieties of bioactivities including antimicrobial,10 anti-inflammation,11 antinociceptive,12 etc. Moreover, more and more studies are emerging recently and suggesting that steroidal alkaloids may have potent activities for the treatment of cancer.13–16 The biological properties of steroidal alkaloids have drawn great interest from researchers to investigate these compounds. While many functional studies have attributed a wide range of biochemical and pharmacological properties to various steroidal alkaloids, there are few reviews to systematically describe the bioactivities, especially anticancer activities, and mechanisms of steroidal alkaloids. In this review, we comprehensively summarize the recent progress on the anticancer profiles both in vitro (Table I) and in vivo (Table II) of steroidal alkaloids. Moreover, other bioactivities of steroidal alkaloids are also discussed. Eventually, we highlight the integrated molecular mechanisms (Table III and Fig. 3) of steroidal alkaloids and contemplate their future prospects as potential drugs.

2. STRUCTURAL FEATURE Steroidal alkaloids possess the basic steroidal skeleton with a nitrogen atom incorporated as an integral part of the molecule, either in a ring or in the side chain.6 In general, steroidal alkaloids have a 21-, 24-, or 27-carbon heterocyclic skeleton, where C21 and C24 alkaloids are also called pregnane and cyclopregnane alkaloids, respectively. The later C27 alkaloids are the most common and important steroidal alkaloids that are derived mainly from the Solanaceae and Liliaceae. The C27 alkaloids differ from other Medicinal Research Reviews DOI 10.1002/med

Leukemia (K562, HL60) Breast cancer (SK-BR-3) Pancreatic carcinoma (PANC-1) Lung cancer (A549)

Sarcovagine D

α-Solanine

23

23 33 31, 42 32, 33 40 33 38 33 34

0.74 0.79–5.53 0.89 2.00–6.60 1.15–11.52 4.60–16.67 ? 3.20–8.60 ? 2.50–7.60 ?

Leukemia (U937, NB4, KG1)

Colon cancer (HCT-8) Cervical cancer (HeLa) Colon cancer (HT-29) Hepatocellular cancer (HepG2) Prostate cancer (PC-3) Gastric cancer (AGS, KATO III) Pancreatic cancer (PANC1, SW1990, PaCa-2) Lymphoma (U937) Melanoma (A2058, A375)

23

23

23 23 23

2.31 2.12 2.56 1.35–2.24

18

18

11.17 16.69

17, 18 17 17

References

2.87–3.53 2.25 2.70

IC50 (μM)

Neuroblastoma (SK-N-SH, SH-SY5Y) Glioma (U87)

Hepatocellular cancer (SMMC-7721) Dendrogenin A Breast cancer (MCF-7) Melanoma (SK-MEL-28) Lung cancer (A549)

Cancer cell lines studied

Steroidal alkaloids

α-Tomatine

Tomatidine

Solamargine

Solasonine

Steroidal alkaloids

Table I. In Vitro Anticancer Effects of Steroidal Alkaloids on Various Cancer Cell Lines

Prostatic cancer (PC-3) Prostatic cancer (PC-3)

Gastric cancer (KATO III)

Gastric cancer (MGC-803) Breast cancer (MCF-7) Colon cancer (HT-29, HCT116) Osteosarcoma (U-2 OS, MG-63, Saos-2) Lung cancer (H441, H520, H661, H69) Glioblastoma (M059J, U343, U251) Hepatocellular cancer (HepG2) Lung cancer (PC-12) Cervical cancer (HeLa) Breast cancer (MCF-7, AU565) Colon cancer (HT-29) Lung cancer (A549)

Glioblastoma (M059J, U343, U251) Lung cancer (PC-12)

References

599.8 2.90

?

5.28 ? 141.7 ? 309.0 ?

9.32–18.78

3.0–7.2

6.0–9.8

? 21.0 ?

?

73 73, 78

73

26, 45, 50 52 14 14, 62, 63 14 15

50

51

69

48 50 45

52

50 45, 47, 50 45, 50, 63, 125 24.57–29.65 50

IC50 (μM)

Cervical cancer (HeLa) 10.84 Breast cancer (MCF7) 25.17 Hepatocellular cancer (HepG2) 6.80

Cancer cell lines studied

THERAPEUTIC POTENTIAL OF STEROIDAL ALKALOIDS

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Medicinal Research Reviews DOI 10.1002/med

33 14 14, 137 14

0.40–1.00 252.5 888.0 725.5 ?

Osteosarcoma (1547)

Medicinal Research Reviews DOI 10.1002/med 76

?

?

Leukemia (HL60, K562)

Lung cancer (H460)

77

137 32

Prostate cancer (PC-3) ? Hepatocellular cancer (HepG2) 2.42–24.2

65

IC50 values may not be comparable across different assays and cells.

Solasodine

32, 33 36 33

0.60–1.17 ? 0.40–0.60

Hepatocellular cancer (HepG2) Lung cancer (A549) Gastric cancer (AGS, KATO III) Lymphoma (U937) Cervical cancer (HeLa) Breast cancer (MCF-7, AU565) Colon cancer (HT-29)

33 31, 42

0.20–0.80 0.12–1.17

Cervical cancer (HeLa) Colon cancer (HT-29)

References

α-Chaconine

IC50 (μM)

Cancer cell lines studied

Steroidal alkaloids

Table I. Continued

Cyclopamine

Steroidal alkaloids

Prostate cancer (PC-3) Colon cancer (HT-29) Hepatocellular cancer (HepG2) Leukemia (HL60, K562, TMD7) Lymphoma (DND-41, Daudi, TMD8) Erythroleukemia (HEL) Lung cancer (A549, H249, H417, H161) Pancreatic cancer (HPAF-2, BxPC-3, Panc-1, AsPC-1, CFPAC-1S2013) Breast cancer (MCF7, BT-474, T-47D, MDA-MB-231, SK-BR-3)

Breast cancer (MDA-MB-231) Gastric cancer (KATO III, AGS) Basal cell carcinoma Medulloblastoma Rhabdomyosarcoma

Cancer cell lines studied

10.0–20.0

8.79–45.09

40.0 4.4–14.4

6.60–13.20

3.0 ? ? 8.20–14.60

? ? ?

25.53 2.94–15.86

IC50 (μM)

86

140

91 84, 138, 139

90

73, 136 32 32 90

98 98 98

73 72, 73

References

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Ip injection

Ip injection Ip injection

Ip injection

Ip injection Multiple injection

Ip injection Sc injection Sc injection Sc injection Sc injection Sc injection

Melanoma and breast cancer in mice

Pancreatic cancer xenografts in athymic mice Sarcoma in mice

MDR sarcoma in mice

Horses with chondrosarcoma

Human with large intracranial squamous cell carcinoma Liver cancer xenografts in athymic mice Leukemia in SCID mice

Medulloblastoma allografts in athymic mice

Small cell lung cancer xenografts in athymic mice

Prostate cancer xenografts in athymic mice

Pancreatic cancer xenografts in athymic mice

Metastatic cholangio carcinoma xenografts in athymic mice

BEC 50 mg/2 occasions/2 days Solamargine 2.4 mg/kg/day α-Tomatine 5 mg/kg/day Cyclopamine 1.25 mg/kg/day Cyclopamine 25 mg/kg/day Cyclopamine 10 mg/kg/day Cyclopamine 25 mg/kg/0.5 day Cyclopamine 50 mg/kg/day

SBHL (15 mg/mL) plus Chemo(CTX 20 mg/mL)/day BEC 100 mg/kg/day

Dendrogenin A 0.37 μg/kg/ 5 day α-Solanine 6 mg/kg/day SBHL 10, 30, 50 mg/kg/day

Effective doses

Eliminate the chondrosarcoma and no recurrence for at least 5 years after treatment The tumor mass is rapidly broken down and erosion interval Inhibit tumor growth without loss of body weight Inhibit leukemia cells growth by surviving inhibition and AIF induction Inhibit xenograft tumor growth by blocking Hh pathway Inhibit xenograft tumor growth by blocking Hh pathway Inhibit xenograft tumor growth by blocking Hh pathway Inhibit xenograft tumor growth and metastasis by blocking Hh pathway Inhibit xenograft tumor growth by blocking Hh pathway

Inhibit tumor growth by decreasing MMP-2/9, PCNA, and VEGF expression Inhibit sarcoma growth by promoting the lymphocyte proliferation, increasing IL-2 production, and enhancing NK and LAK cells activities Reverse the acquired multidrug resistance of S180 tumor by reducing P-gp, LRP, and Topoisomerase II expression

Inhibit cholesterol epoxide hydrolase

End point or mechanisms of action

89

88

87

84

82

76

57

58

58

56

55

38

24

References

MMP, matrix metalloproteinases; PCNA, proliferating cell nuclear antigen; VEGF, vascular endothelial growth factor; SBHL, solasodine hydrochloride; MDR, multidrug resistant; Ip, intraperitoneal; Sc, subcutaneous; NK, natural killer; LAK, lymphokine-activated killer cell; P-gp, P-glycoprotein; LRP, lung resistance protein; SCID, severe combined immunodeficiency disease mice; AIF, apoptosis-inducing factor; Hh, Hedgehog; ICR, Institute of Cancer Research.

Ip injection

Administration

Models

Table II. In Vivo Anticancer Effects of Steroidal Alkaloids

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r 5

Medicinal Research Reviews DOI 10.1002/med

Tomatidine Solamargine α-Tomatine Cyclopamine α-Chaconine α-Solanine Cortistatins J, K, L Solamargine Tomatidine α-Tomatine α-Chaconine α-Solanine Cyclopamine

↓ PI3K; ↑↓ Akt; ↓ ERK; ↓ JNK;↓ NF-κB; ↓ IκBα; ↓COX-2; ↓ NOS; ↓ Oct-2;↓ p53; ↑ TNF-α; ↑ TNF-β; ↑ Fas; ↑ FADD; ↑ TRADD

↓ VEGE; ↓ bFGF; ↓ HER2

↓ MMP-2; ↓ MMP-9; ↓ FAK; ↑ RECK; ↑ TIMP-1

↓ Smo; ↓ Gli-1; ↓ Ptch

Inhibition of proliferation and inflammation

Inhibition of angiogenesis

Medicinal Research Reviews DOI 10.1002/med

Inhibition of metastasis

Inhibition of Hh signaling pathway

84, 90, 92, 98, 101, 142 ROS, reactive oxygen species; PARP, poly(ADP-ribose) polymerase; AIF, apoptosis-inducing factor; PI3K, phosphoinositide-3 kinase; ERK, extracellular signal regulated kinases; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor kappa B; COX-2, cyclooxygenase-2 enzyme; TNF, tumor necrosis factor; FADD, Fas-associated death domain; TRADD, TNFR-1-associated death domain; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; HER2, human epidermal growth factor receptor 2;MMP, matrix metalloproteinases; FAK, focal adhesion kinase; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; TIMP-1, TIMP metallopeptidase inhibitor 1.

15, 34, 36, 40, 77

25,141

15, 34, 36, 51, 73, 76–78, 91, 110

48, 51, 69, 76–78, 91, 92

Solamargine α-Tomatine Cyclopamine Jervine

Induction of apoptosis

82, 87

Cyclopamine

↓ Cyclin D1; ↓ Cyclin D2; ↓ Cyclin E1; ↓ N-myc; ↓ C-myc; ↓ L-myc ↑ ROS; ↑ Caspase-3; ↑ Caspase-8; ↑ Caspase-9; ↑ Cytochrome C; ↑PARP; ↓ Bcl-2; ↓ Bcl-xL; ↑ Bax; ↓ Survivin; ↑ Mcl-1; ↑ AIF

Induction of cell-cycle arrest

References

Steroidal alkaloids

Molecular targets

Molecular mechanisms

Table III. Molecular Targets of Steroidal Alkaloids for the Treatment of 1Cancer

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skeleton type and can be divided into two types, cholestane alkaloids and C-nor-Dhomosteroidal alkaloids. Structurally these alkaloids are classified into three major groups: solanidanes, spirosolanes, and jervanes. Solanidanes and spirosolanes are true steroids that belong to cholestane, whereas in jervanes the rings are rearranged to form a C-nor-Dhomosteroid.6 The chemical structures of the representative steroidal alkaloids are shown in Figure 2.

3. ANTICANCER EFFECTS A. Pregnane Alkaloids The pregnane-type steroidal alkaloids are mainly distributed in many genus of the Apocynaceae, and mostly display significant cytotoxicities against tumor cells. Sarcovagine D and sarcorucinine A1, two main pregnane steroidal alkaloids isolated from Sarcococca saligna, show strong cytotoxic potential against human breast cancer SK-BR-3, leukemia K562, and pancreatic cancer PANC-1 cells, with the IC50 values ranging from 2.25 to 5.00 μM. While sarsaligenines A and sarsaligenines B selectively inhibit cell growth of human leukemia HL60 cells with the IC50 values of 2.87 and 3.61 μM, respectively.17 In addition, Sun et al. have demonstrated that sarcovagine D possesses moderate inhibitory activities against various human cancer cells including leukemia HL60, pancreatic cancer PANC-1, lung cancer A549, and hepatocellular cancer SMMC-7721 cells with the IC50 values ranging from 2.96 to 16.69 μM.18 Three pregnane alkaloids 3-O-acetylveralkamine, veralkamine 3-(b-Dglucopyranoside), and 6,7-epoxyverdine from Veratrum taliense show cytotoxic to various human cancer cells including leukemia HL60, hepatocellular cancer SMMC-7721, lung cancer A549, breast cancer MCF-7, and colon cancer SW480 cells.33 Recently, six new pregnane alkaloids terminamines A–E, H, and seven known alkaloids isolated from Pachysandra terminalis, significantly inhibit the migration of human breast cancer MB-MDA-231 cells induced by epithelial growth factor.13, 34 In addition, four pregnane-type steroidal alkaloids epipachysamines B and E, pachystermine A and E, isolated from the methanol extract of the stems of P. terminalis, show cytotoxicity against mouse leukemia P388 and its doxorubicinresistant P388/ADR cells in vitro.35 Another pregnane alkaloid wrightiamine A from Wrightia javanica is also cytotoxic to vincristine-resistant P388 cells.29 Interestingly, a chemically synthesized alkylaminooxysterol dendrogenin A induces cell differentiation and death in various cancer cells.30 Furthermore, dendrogenin A works as a potent inhibitor of cholesterol epoxide hydrolase to induce tumor differentiation and growth control in mice and prolong animal survival.31

B. Cyclopregnane Alkaloids Cortistatins, a type of cyclopregnane alkaloids isolated from the marine sponge Corticium simplex, significantly inhibit cell growth, vascular endothelial growth factor induced migration, and basic fibroblast growth factor induced tubular formation in human umbilical vein endothelial HUVEC cells.32 Additionally, cortistatins (A, E–L) also show significant antiproliferative activity against human oral carcinoma KB-3–1 and leukemia K562 cells with the IC50 values ranging from 2.3 to 14 μM.32–35 Recently, the cyclopregnane alkaloid cyclovirobuxine D (CVBD) is able to induce autophagy-associated cell death by attenuating the phosphorylation of Akt and mTOR in human breast cancer MCF-7 cells.36 Medicinal Research Reviews DOI 10.1002/med

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Figure 2.

The chemical structures of representative steroidal alkaloid.

Medicinal Research Reviews DOI 10.1002/med

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Figure 3.

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The potential anticancer mechanism of steroidal alkaloids.

C. Cholestane Alkaloids 1. Solanidanes Solanidine, a representative solanidane of steroidal alkaloids, abundantly exists in potato sprouts (S. tuberosum L).37 α-solanine and α-chaconine are two main alkaloids of solanidine with a carbohydrate side chain. The side chain of α-chaconine is composed of glucose and two rhamnose molecules, and that of α-solanine is composed of glucose, galactose, and rhamnose (Fig. 2).38 It has been reported that these alkaloids are potent to inhibit proliferation and induce apoptosis in various type of cancer cells in vitro.32–44 Furthermore, α-solanine shows the obvious antitumor effect on in vivo xenograft models of breast and pancreatic cancer through inhibition of cell proliferation, metastasis, and tumor angiogenesis.45, 46 Moreover, the effectiveness of α-chaconine against hepatocellular cancer HepG2 cells is higher than the common anticancer agents doxorubicin and camptothecin.39 Interestingly, α-solanine and α-chaconine exhibit the synergism cytotoxicity against hepatocellular cancer HepG2 and gastric cancer AGS cells, laying the foundation for further clinical combination therapy.40 Matrix metalloproteinases (MMPs) are the major proteases involving in cancer cells migration, invasion, and metastasis.47 Several studies have found that both α-solanine and α-chaconine inhibited the expression and activity of MMP-2 and MMP-9 to suppress the migration and invasion of cancer cells.41, 42, 45, 47 It is known that MMP-2 and MMP-9 expressions are critically regulated by PI3K/Akt and MAPK pathways.48, 49 α-solanine and α-chaconine can significantly decrease the phosphorylation level of Akt and ERK, indicating that PI3K/Akt and MAPK signaling pathways are suppressed by α-solanine and α-chaconine.41, 42, 45 In addition, α-solanine and α-chaconine can also inhibit the NF-κB activity, which is a key transcriptional factor to suppress metastasis.41, 42 Interestingly, α-solanine can downregulate the expression of miR21, which is a microRNA playing an important role in tumor initiation and progression.47 Furthermore, Yang et al. have shown that α-chaconine induces cell apoptosis through inhibition of ERK and in turn, activation of caspase-3.50 Recently, Zupko et al. have reported that some solanidine analogues are able to inhibit the activities of topoisomerase I and P-glycoprotein (P-gp) to carry out anticancer and multidrug resistant (MDR) reversal effects on cancer cells.44 Medicinal Research Reviews DOI 10.1002/med

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2. Spirosolanes Solasodine Solasodine is one of important alkaloids found in a large number of Solanum species.51 Solasodine with different carbohydrate moieties can form various glycoalkaloids. The two glycosides of solasodine, solasonine, and solamargine differ only in their carbohydrate moieties (Fig. 2). Solamargine and solasonine are effective in the treatment of human malignant skin cancers including basal and squamous cell carcinomas.52, 53 Moreover, solamargine also displayed significant cytotoxicities against human breast cancer MCF-7, hepatocellular cancer HepG2, glioblastoma U87, colon cancer HCT116, leukemia K562, cervical cancer HeLa, lung cancer A549 cells with IC50 values of 2.1, 2.5, 3.2, 3.8, 5.2, 6.0, and 8.0 μM, respectively, and a lower cytotoxicity to human normal hepatocyte HL7702 and rat normal cardiomyoblasts H9C2 cells (IC50 values of 13.5 and >20 μM, respectively). 54 Several recent reports have also suggested that solasodine and its derivatives have potent cytotoxicity against human lung, gastric, colon, breast, glioblastoma, hepatocellular, and cervical cancer cells. 14, 55–59 Ono et al. have found that solamargine when compared to cisplatin has more potent antiproliferative activity against human leukemia HL60 cells.60 Similarly, solamargine is more cytotoxic against breast cancer cells than cisplatin, methotrexate, 5-fluorouracil, epirubicin, and cyclophosphamide.61 The in vivo antitumor activity of solasodine hydrochloride (SBHL) has been evaluated in mice transplanted with sarcoma S180 tumor. The intraperitoneal injection of 30, 50 mg/kg/d of SBHL for 14 days results in significant tumor reduction by 67.4 and 80.1%, respectively.62 Furthermore, treatment with SBHL (15 mg/mL) in combination of cyclophosphamide (20 mg/mL) for 4 weeks obviously inhibits the growth of MDR sarcoma S180 tumor in mice.63 Follow-up studies have demonstrated that in addition to inducing cell apoptosis, the combination chemotherapy significantly downregulates the expression of Topoisomerase II, P-gp, and lung cancer resistance protein.63 Another study has displayed that intravenous injection of solamargine (2.4 mg/kg) distinctly inhibits the growth of hepatocellular cancer H22 (57.37%) or Ehrlich ascites tumor (67.55%) in mice.64 Recently, it is shown that the cream formulation of BEC (a mixture of solasodine rhamnosyl glycosides, solamargine 33%, solasonine 33%, and their corresponding di- and monoglycosides 34%) is effective on treating squamous cell and nonmelanoma basal cell carcinomas.59, 65 In one study, intralesional injection of BEC has been used to treat chondrosarcomas with multiple squamous cell carcinoma lesions on the penis in one horse while another had a large intracranial squamous cell carcinoma. Both the horses remarkably respond to the treatment with a large proportion of the tumor mass completely eliminated, and there is no recurrence for at least 5 years.65 Another study with BEC treatment of 11 squamous cell carcinoma patients and eight basal cell carcinoma patients shows similar findings of complete eradication of tumor. The BEC is well tolerated in these patients, and there are no signs of residual cancer during the histopathological and periodic clinical assessment of treated patients within 5 years posttreatment.66 Moreover, the cream formulation CuradermBEC5 containing the BEC at 0.005% is specific, effective, and safe for the treatment of skin cancers.9, 67, 68 In a Phase IIb clinical trial with 94 basal cell carcinoma patients, the efficacy and safety of another 0.005% mixture of solasodine glycosides (mainly solasonine and solamargine) cream named Zycure has been investigated, and the results demonstrated that Zycure is a safe treatment for basal cell carcinoma with a final cure rate of 66% (41/62) at 8 weeks and 78% (29/37) at 1-year followup.69 In a phase I clinical trials of Coramsine (a 1:1 mixture of solasonine and solamargine) in 27 patients with advanced solid tumors, Coramsine causes dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hr or 1.5 mg/kg/day over 4 hr and the maximum tolerated dose above 2.25 mg/kg/day over 24 hr, and the pharmacokinetic parameters of solasonine and solamargine are calculated as the elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± Medicinal Research Reviews DOI 10.1002/med

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2.00 hr (solamargine), Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine), and both peak levels >2000 ng/mL.70 These results are quite encouraging and indicate that these solasodine glycosides may be potential drugs to effectively treat skin cancer or advanced solid tumors without any significant adverse effects. It is well accepted that most anticancer agents execute their anticancer effects by inducing cell apoptosis.71 Trouillas et al. have observed DNA fragmentation when human osteosarcoma 1547 cells are treated with solasodine, suggesting apoptosis induction.72 Solamargine can significantly induce cell shrinkage and apoptosis by upregulating the expression of tumor necrosis factor receptors (TNFRs), and therefore enhanced the binding of TNF-α and TNF-β to the lung cancers.58 Mechanistically, solamargine causes the G2/M phase arrest in human lung cancer and normal hepatocyte cells,58, 73, 74 and triggers cell apoptosis by upregulating the expression of caspase-3 and caspase-9, downregulating the expression of Bcl-2 and Bcl-xL, and activating lysosomal–mitochondrial pathway.58, 61, 75 Furthermore, solamargine upregulates the expression of external death receptors, such as TNFR-1, TNFR-1-associated death domain (TRADD), Fas-associated death domain (FADD), and Fas receptor,61 and induces mitochondrial translocation of p53, release of cytochrome c, as well as activation of caspase-3 and caspase-9.76 These findings suggest that the mitochondria-mediated apoptotic pathway is activated by solamargine via both p53-dependent and p53-independent mechanisms. Moreover, solamargine shows nearly equal to or even more potent cytotoxicity against MDR cancer cells compared with the corresponding parental non-MDR cancer cells.77

Tomatidine Tomatidine, and its glycosides α-, β-, γ -, and δ-tomatine are mainly found in the stems, leaves, and fruits of tomato plants. Their chemical structures are shown in Figure 2. The levels of tomatine in the immature green tomatoes are 48 mg/kg of fresh weight and 743 mg/kg of dry weight, while in mature red tomatoes they are only 0.4 mg/kg of fresh weight and 0.7 mg/kg of dry weight, respectively.78 A number of studies have reported the anticancer potential of tomatidine and tomatines in various cancer cells.15, 60, 79, 80 Tomatidine can arrest cancer cells in G0/G1 cell cycle phase and thus exhibited significant inhibitory effects on human cervical cancer HeLa, breast cancer MCF-7, and colon cancer HT-29 cells.14 Similarly, tomatidine shows cytotoxicity against human breast epithelial HBL-100 cells,81 and markedly inhibits invasion of human lung cancer A549 cells.15 In addition, it is reported that nontoxic concentrations of tomatidine potently chemosensitizes MDR cancer cells, suggesting that tomatidine has a potential to be used in combination with chemotherapeutic drugs for the treatment of MDR cancer.82 α-Tomatine shows significant cytotoxicities in human leukemia HL60 and K562 cells,83 and lung cancer NCI-H460 cells.84 The intraperitoneal administration of α-tomatine (5 mg/kg/day) in HL60 cells xenograft mice model, after the tumor has reached palpable size of around 100 mm3 , results in obvious tumor shrinkage without any observable toxicity or weight loss. Notably, there is increased apoptosis-inducing factor expression and reduced survivin expression in the treated mice tumor tissues.83 The IC50 of α-tomatine against human gastric cancer AGS, colon cancer HT-29, and breast cancer MCF-7 cells are 0.03, 0.03, and 5.07 mg/mL, respectively, suggesting that α-tomatine is distinctly cytotoxic to first two cancer cells mentioned above.79 Human prostatic cancer PC-3 cells are also highly susceptible to α-tomatine, and it killed PC-3 cells even after 1 hr of treatment compared with the lower cytotoxicity or nontoxicity in normal liver or prostate cells.85 Interestingly, β-, γ -, and δtomatine are more cytotoxic than tomatidine in human gastric cancer KATO III, breast cancer MDA-MB-231, and prostate cancer PC-3 cells.80 These observations suggest that the presence of carbohydrate moiety may enhance the cytotoxicity of tomatidine. Medicinal Research Reviews DOI 10.1002/med

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Currently, the anticancer mechanisms of tomatidine and its derivatives are not clearly understood, and it may be an area of intense interest for pharmacologists. Tomatidine can significantly inhibit the function of ABC transporters and thus effectively reverse MDR in carcinoma cells,82 and upregulate the expression of tissue inhibitor of metalloproteinase-1 (TIMP1) and cysteine-rich protein with kazal motifs (RECK), while downregulate the expression of MMP-2/9 to inhibit the migration and invasion of A549 cancer cells.15 In addition, tomatidine markedly reduces Akt and ERK phosphorylation, suggesting that the downstream signaling pathways of Akt and ERK are potentially suppressed by tomatidine.15 α-Tomatine displays potent antimetastatic effect on cancer cells possibly through inactivation of PI3K/Akt signaling pathway, downregulation of FAK phosphorylation, and reduction of NF-κB DNA-binding activity by enhancing the inhibitor of kappa Bα (IκBα) protein expression.84 Furthermore, α-tomatine can induce apoptosis by activation of caspase-3, caspase-8, and caspase-9, Mcl-1 and Bak,85 and alter the mitochondrial membrane potential by directly activating the permeability transition pore complex. 83 These findings indicate that α-tomatine induces cancer cell apoptosis mainly through caspase-dependent pathway.

D. C-nor-D-Homosteroidal Alkaloids 1. Cyclopamine Cyclopamine, a kind of C-nor-D-homosteroidal alkaloid, was first identified as potent teratogens in animals.86 Structurally related compounds include jervine, veratramine, and KAADcyclopamine (Fig. 2). It has been characterized that cyclopamine is a Hedgehog (Hh) signaling pathway antagonist, which indicates its role in the induction of teratogenicity.87 Numerous studies have investigated the anticancer effects of cyclopamine and their derivatives in vitro and in vivo. Veratramine and jervine can significantly inhibit migration and proliferation of prostate cancer and other cancer cells.88 The IC50 values of the veratramine against human lung cancer NCI-H249 and A549, pancreatic cancer PANC-1 and SW1990 cells were 8.5, 8.9, 14.5, and 26.1 μM, respectively.16 Berman et al. have examined the anticancer effects of cyclopamine on preclinical cellular and animal models of medulloblastoma, and showed that cyclopamine significantly inhibits the proliferation of murine medulloblastoma and primary human medulloblastomas cells in vitro and distinctly minimizes murine allografts tumor in vivo.89 Furthermore, cyclopamine also shows prominent anticancer effects on epithelial tumors, including basal cell carcinoma,90 lung cancer,91 oral squamous cell carcinoma,92 breast cancer,93 prostate cancer,94 several digestive tract neoplasms such as oesophagus, stomach, biliary tract, and pancreas cancers,95, 96 and leukemia.97 Mechanistically, cyclopamine and its analogues are multitargeted in nature. Cyclopamine can modulate Akt and ERK pathways to inhibit NF-κB pathway and stimulate PKC activation to upregulate cyclooxygenase-2 (COX-2) expression and induce apoptosis.98 Furthermore, cyclopamine also induces apoptosis through inhibition of Shh signaling pathway and downregulation of Bcl-2 in hepatocellular cancer PLC/PRF/5, Huh7, and SMMC-7721 cells.99 Berman et al. have found that cyclopamine is able to reduce the expression of Cyclin D1, D2, E1, hyperphosphorylated Rb, N-, C-, and L-myc, and upregulated the expression of NeuroD.89 Additionally, cyclopamine can reverse MDR by blocking the function of P-gp transporter and therefore may be beneficial in combination chemotherapy with conventional anticancer agents against MDR cancer.82 Hh pathway plays a crucial role in the embryonic development of multiple tissues and contributes to tissue homeostasis in adults, and uncontrolled activation of Hh signaling is closely related to the initiation and progression of multiple cancers.100–104 Cyclopamine and their derivatives are selective Hh signaling antagonists that mainly targets Smoothened Medicinal Research Reviews DOI 10.1002/med

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(Smo) receptors. Berman et al. have reported that cyclopamine and KAAD-cyclopamine can target Smo to inhibit the proliferation of cancer cells in vitro and in vivo.89 Taipale et al. have confirmed that cyclopamine and its derivatives can inhibit Hh pathway through antagonizing Smo, and KAAD-cyclopamine are more potent than cyclopamine to block the activation of Hh pathway by oncogenic mutation.105 Exo-cyclopamine, another analogue of cyclopamine, also displays potent Hh pathway inhibitory activity in a Gli-dependent reporter assay.106, 107 Veratramine shows much weaker activity than cyclopamine to inhibit Hh pathway, while cyclopamine-4-en-3-one, an oxydate of cyclopamine, increases potency by at least twofold.108 In addition, cyclopamine can inhibit cell growth and induce apoptosis in various leukemia and lymphoma cells, and decrease the expression of Gli1 that is a target gene of Hh signaling.97 However, cyclopamine and its derivant CUR0199691 are able to suppress the cell growth of either estrogen receptor (ER) positive or ER-negative breast cancer cells in an independent Smo manner, suggesting there are other molecular targets required for growth inhibition of cyclopamine and CUR0199691.93 These promising findings may lay the foundation for the development of cyclopamine and its derivatives as potent anticancer agents.

4. OTHER BIOLOGICAL EFFECTS A. Antimicrobial Effects Steroidal alkaloids have shown a wide spectrum of antibacterial effects in many previous studies. Two new steroidal alkaloids saligcinnamide and N(a)-methyl epipachysamine-D, isolated from S. saligna, possess potent antibacterial activity against seven human pathogenic bacteria including Streptococcus pyogenes, Klebsiella pneumonia, Staphylococcus aureus, Proteus mirabilis, Salmonella typhii, Shigella boydii, and Pseudomonas aeruginosa.109 Mitchell et al. have characterized the activities of tomatidine against S. aureus, and found that aminoglycosides antibiotics in combination with tomatidine show synergistically efficacious bacteriocidal effects.110 Solasodine is able to directly or indirectly interfere with the synthesis and function of genetic substances in Saccharomyces cerevisiae and Prototheca wickerhamii.10 Furthermore, solasodine has inhibitory effects on the growth of Geim original algal.111 Although the mechanism is not very clear, it is suggested that solasodine is able to affect the fungus genetic material synthesis, leading to cell-cycle arrest, and finally, resulting in fungus growth arrest or even death.111 In another study, two new and 13 known steroidal alkaloids from Liliaceae exhibited significant antifungal activities against the phytopathogenic fungus Phytophthora capisis with the MICs ranging from 0.08 to 0.12 μg/mL.111 Solanine also shows remarkable antifungus activity against Aspergillus niger, Candida albicans and moderate activity against a few other fungi. In addition, Ito et al. have demonstrated that α-tomatine induces cell apoptosis of Fusarium oxysporum through activation of tyrosine kinase and monomeric GTP-binding protein signaling pathways, leading to Ca2+ elevation and reactive oxygen species burst in F. oxysporum cells.112 Devkota et al. have reported that five steroidal alkaloids from S. hookeriana have moderate antiplasmodial activity (IC50 2.4–10.3 μM) against Plasmodium falciparum chloroquine-resistant W2 strain.113 Ten 5α-pregnane-type steroidal alkaloids from S. hookeriana show effective leishmanicidal effects on Leishmania major in vitro, and sarcovagine C has the highest potency (IC50 1.5 μM) compared with the positive control pentamidine (IC50 7.5 μM).114 Recently, didehydro-Cortistatin A (dCA), an analogue of cortistatin, is able to inhibit both HIV-1 and HIV-2 replication by reducing Tat-dependent HIV transcription in either acutely or chronic infected cells, and decrease residual viremia during highly active antiretroviral therapy, suggesting dCA may be a unique type of anti-HIV agent.115 Medicinal Research Reviews DOI 10.1002/med

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B. Anti-Inflammatory and Antinociceptive Effects Solasodine has been examined for its anti-inflammatory activity against paw edema in rats induced by carrageenan, and the results exhibit obvious decrease of the inflammatory reaction from 19.5 to 56.4% of paw volume after solasodine treatment.11 In addition, solasodine has been evaluated for its antinociceptive activity by the hot plate, formalin, and writhing tests, and the results indicate that solasodine can significantly reduce the nociception caused by intraperitoneal injection of formalin and acetic acid.12 α-Chaconine and solanidine also display the anti-inflammatory effects by reducing the production of interleukin-2 and interleukin-8 in concanavalin-A-induced human T lymphocyte Jurkat cells, and the production of nitric oxide (NO) by lipopolysaccharide (LPS) stimulated macrophages.116 Furthermore, Chiu et al. have demonstrated that tomatidine has better anti-inflammatory effect than solasodine on the LPS-stimulated mouse macrophages through inhibition of NF-κB nuclear translocation, IκBα phosphorylation, and JNK activation to decrease the expression of COX-2 and inducible NO synthase.117 C. Antiestrogenic and Antiandrogenic Effects Nine steroidal alkaloids ((+)−(20S)-20-(dimethylamino)-3-(3 α-isopropyl)-lactam-5α-pregn2-en-4-one, (+)−(20S)-20-(dimethylamino)-16α-hydroxy-3-(3 α-isopropyl)-lactam-5α-pregn2-en-4-one, (+)−(20S)-3-(benzoylamino)-20-(dimethylamino)-5α-pregn-2-en-4β-yl acetate, (+)−(20S)-2α-hydroxy-20-(dimethylamino)-3β-phthalimido-5α-pregnan-4β-yl acetate, (−)pachyaximine A, (+)-spiropachysine, (+)-axillaridine A, (+)-epipachysamine D, and (+)pachysamine B) isolated from P. procumbens possess significant antiestrogenic activity in an ER-binding assay with the IC50 values ranging from 0.4 to 8.0 μM.118 Other seven steroidal alkaloids ((+)-(20S)-20-(dimethylamino)-3α-(methylbenzoylamino)11-methylene-5α-pregnane, (+)-(20S)-3-(benzoylamino)-20-(dimethylamino)-5α-pregn-2-en4β-ol, (+)-(20S)-20-(dimethylamino)-16α-hydroxy-3β-(3 α-isopropyl)-lactam-5α-pregn-4-one, (+)-(20S)-20-(dimethylamino)-3α-(methylbenzoylamino)-5α-pregn-12β-yl acetate, (+)-(20S)20-(dimethylamino)-3α-(methylsenecioylamino)-5α-pregn-12β-ol, (+)-pachysamine H, and (+)-pachysandrine B) also have antiestrogenic effects in an estrone sulfatase inhibition assay, and two of them ((+)-(20S)-3-(benzoylamino)-20-(dimethylamino)-5α-pregn-2-en-4β-ol) and ((+)-(20S)-20-(dimethylamino)-3α-(methylsenecioylamino)-5α-pregn-12β-ol) show more potent antiestrogenic activity (IC50 values of 0.11 and 0.41 μM, respectively) than the positive control danazol (IC50 3.8 μM).119 It is noteworthy that oral administration of solasodine to normal dogs clearly induces atrophy of epithelial cell of cauda epididymides and loss of spermatozoa in the lumen.120 In addition, castration followed by the treatment with solasodine has more remarkable atrophy of epithelial cells of cauda epididymides compared to castrated controls. Furthermore, the total protein, glycogen, sialic acid, and acid phosphatase activities are markedly decreased in cauda epididymides after solasodine treatment.120 These results indicate that solasodine and its analogues may have potent antiandrogenic effects. D. Antithrombotic and Antiarrhythmia Effects Cyclovirobuxine D (CVB-D), a cyclopregnane-type alkaloid isolated from Chinese traditional medicine plant Buxus microphylla, is broadly applied in China for the treatment of cardiovascular and cerebrovascular diseases.114–124 In rats, CVB-D can significantly increase NO release from endothelial cells and cardiomyocytes viability, decrease the infarct size caused by blocking the coronary artery and the weight of venous thrombus, and protect the aorta endothelial cells against hypoxia. The main cytoprotective function of CVB-D on myocardial ischemia Medicinal Research Reviews DOI 10.1002/med

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may be attributed to inhibiting venous thrombosis, stimulating NO generation, and opening ATP-sensitive potassium channel.125 Recently, CVB-D has also been reported to possess antiarrhythmia activity by prolonging the effective refractory period of ventricular muscle and action potential duration.126 Additionally, the data from a study in rats with congestive heart failure show outstanding benefit after treating with CVB-D, suggesting that it may be helpful in therapeutic application against cardiac dysfunction.127

E. Toxicity The veratrum alkaloids are one of the well-known teratogenic agents to induce holoprosencephaly in mammals, while cyclopamine and jervine have potent teratogenic activity to cause synophthalmia in rabbits, rats, mice, hamsters, and sheeps.29, 86, 128, 129 In mice, cyclopamine exposure also induced lateral cleft lip and palate defects, and its analog AZ75 exposure caused alobar and semilobar holoprosencephaly.70 Solasodine can also be teratogenic, because it induces spina bifida, exencephaly, and cranial bleb in hamsters.130 Furthermore, α-chaconine and α-solanine show neurological toxicities, that is, spina bifida and other malformations in the frog embryo.131 In addition, α-chaconine may be hepatotoxic due to its ability to induce significant cytotoxicity in normal human liver Chang cells.39 Mechanistically, the toxicity of αchaconine and α-solanine may be caused by inhibition of the activity of cholinesterase enzymes in humans central nervous system and disruption of cell membranes in the gastrointestinal tract.132–134 Structure–activity analysis suggests that the presence of C-5, C-6 unsaturation in the steroidal framework of jervanes, solanidanes, and spirosolanes is responsible for their teratogenicity, which is further aggravated if C-5, C-6 are an olefinic linkage.131 Moreover, three steroidal glycoalkaloids solasodine, solanidine, and tomatidine are able to induce hepatomegaly in both pregnant and nonpregnant mice fed for 2 weeks with a diet containing these aglycones.135

F. Miscellaneous Effects Five novel pregnane-type steroidal alkaloids (5,14-dehydro-N(a)-demethylsaracodine, 14dehydro-N(a)-demethylsaracodine, 16-dehydrosarcorine, 2,3-dehydrosarsalignone, and 14,15dehydrosarcovagine-D) extracted from S. saligna and two known sarcovagenine-C and salignarine-C can potently inhibit the activities of both acetylcholinesterase (IC50 values ranging from 12.5 to 200 μM) and butyrylcholinesterase (IC50 values ranging from 1.25 to 32.2 μM).136 Additionally, α-chaconine and α-solanine clearly suppress both human and bovine acetylcholinesterase activities at a relatively higher concentration of 100 μM.137 The cholinesterase inhibitory effect of other steroidal alkaloids has been confirmed in other studies as well.113, 138 An analogue of jervine O-acetyljervine induces a concentration-dependent reduction in blood pressure and tachycardia in anesthetized normotensive rats.139 Veratroylgermine, another steroidal alkaloid, is able to inhibit the platelet aggregation induced by arachidonic acid with 92.0% inhibition rate at the concentration of 100 μM.140 Three steroidal alkaloids, ebeiensine, ebeiedine, and hupeheninoside, isolated from Fritillaria hupehensis, have been examined for their antiasthmatic and antitussive activity, and the results show that ebeiensine exhibited significant antitussive activity on ammonia liquor induced cough in mice at a dosage level of 3.3 mg/kg, while ebeiedine and hupeheninoside have distinct antiasthmatic effect on acetylcholine chloride/histamine-induced asthma in the guinea pig at a dosage level of 3 mg/kg.141 In addition, steroidal alkaloids isolated from S. paniculatum protect cells against mitomycin C aneugenic and clastogenic actions.142 Medicinal Research Reviews DOI 10.1002/med

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5. SUMMARY Steroidal alkaloids are the natural nitrogen-containing compounds that are present in many edible or medicinal plants. Recent thrust in this field has demonstrated that these natural alkaloids and their semisynthetic products have a wide spectrum of biological activities. Specially, steroidal alkaloids have significant and potent anticancer effects on various types of cancers, including osteosarcoma, glioblastoma, breast, gastric, colon, liver, lung cancer among others. Although the detailed mechanisms of multiplex bioactivities of steroidal alkaloids are unclear, the major molecular targets of steroidal alkaloids for the treatment of cancer are summarized in Table III and Figure 3. For instance, the solanidane-type steroidal alkaloids inhibit the migration and invasion of cancer cells by suppressing PI3K/Akt/NF-κB signaling pathway to reduce MMP-2/MMP-9 expressions and activities.43, 47 The solasodine type of steroidal alkaloids increase the expression of TNFRs and the proteins in the downstream signaling pathway of FADD and TRADD, release cytochrome C, and decrease the expression of antiapoptotic proteins, such as Bcl-2 and Bcl-xL.14, 58, 61 While the main mechanism of solasodine-induced apoptosis is likely through both p53-dependent and p53-independent mechanisms. Tomatidine suppresses the invasion of cancer cells by inhibiting ERK and Akt signaling pathways to upregulate RECK and TIMP-1 expression and downregulate MMP-2/MMP-9 expression. 15 Cyclopamine and related compounds can suppress Hh signaling by antagonizing Smo, which in turn inhibit cancer cells proliferation driven by either Smo or Ptch mutations.105 Additionally, cyclopamine inhibits NF-κB pathway and stimulates PKC activation to induce both COX-2 overexpression and apoptosis.98 Furthermore, specific steroidal alkaloids in combination with cytotoxic agents has synergistically anticancer effect and even overcome MDR in cancer cells.82 Although the therapeutic potential of steroidal alkaloids looks promising in in vitro and in vivo preclinical studies and the encouraging clinical trials from this review, several hurdles exist in the current stage. Toxicity especially teratogenicity is an important issue with steroidal alkaloids. It is worth to synthesize derivatives of steroidal alkaloids with more selectivity and efficacy, and to reduce the unexpected side effects. Additionally, there is little literature related to the pharmacokinetic profiles of steroidal alkaloids including absorption, distribution, metabolism, and excretion. Therefore, further pharmacokinetic and clinical studies are mandated to define the efficacy and safety of steroidal alkaloids in cancer and other diseases. ACKNOWLEDGMENTS This work was supported by funds from the National Natural Science Foundation of China No. 31271444 and No. 81201726 (Z.S.), No. 31171304 (X.W.), No. 81303305 (K.C.), the Guangdong Natural Science Funds for Distinguished Young Scholar No. 2014A030306001 (Z.S.), the Science and Technology Program of Guangzhou No. 2014J4100009 (Z.S.), the Macao Science and Technology Development No.102/2012/A3(M.C.) and Lishui Science and Technology Bureau Research Fund No. 20140212037 (K.C.). CONFLICT OF INTEREST The authors declared no conflicts of interest. REFERENCES 1. Dohadwalla AN. Natural product pharmacology: Strategies in search of leads for new drug designs. Trends Pharmacol Sci 1985;6:49. Medicinal Research Reviews DOI 10.1002/med

THERAPEUTIC POTENTIAL OF STEROIDAL ALKALOIDS

r 17

2. Yan XJ, Gong LH, Zheng FY, Cheng KJ, Chen ZS, Shi Z. Triterpenoids as reversal agents for anticancer drug resistance treatment. Drug Discov Today 2014;19(4):482–488. 3. Xue YQ, Di JM, Luo Y, Cheng KJ, Wei X, Shi Z. Resveratrol oligomers for the prevention and treatment of cancers. Oxid Med Cell Longev 2014;2014:765832. 4. Stanton RA, Gernert KM, Nettles JH, Aneja R. Drugs that target dynamic microtubules: A new molecular perspective. Med Res Rev 2011;31(3):443–481. 5. Wall ME. Camptothecin and taxol: Discovery to clinic. Med Res Rev 1998;18(5):299–314. 6. Rahman A, Choudhary MI. Chemistry and biology of steroidal alkaloids. In: Cordell GA, Ed. The Alkaloids: Chemistry and Biology, Vol. 50. New York: Elsevier; 1998. p 61–108. 7. Atta ur R, Choudhary MI. Diterpenoid and steroidal alkaloids. Nat Prod Rep 1997;14(2):191–203. 8. Li HJ, Jiang Y, Li P. Chemistry, bioactivity and geographical diversity of steroidal alkaloids from the Liliaceae family. Nat Prod Rep 2006;23(5):735–752. 9. Van Gelder W, Vinke J, Scheffer J. Steroidal glycoalkaloids in tubers and leaves of Solanum species used in potato breeding. Euphytica 1988;39(3):S1478–S1158. 10. Wang LD, Guo DA, Yuan L, He QH, Hu YQ, Tu PF, Zheng JH. Antifungal effect of three natural products on the genetic substance of Saccharomyces cerevisiae GL7 and Prototheca wickerhamii. Yao Xue Xue Bao 2000;35(11):860–863. 11. Emmanuel S, Ignacimuthu S, Perumalsamy R, Amalraj T. Antiinflammatory activity of Solanum trilobatum. Fitoterapia 2006;77(7–8):611–612. 12. Pandurangan A, Khosa RL, Hemalatha S. Antinociceptive activity of steroid alkaloids isolated from Solanum trilobatum Linn. J Asian Nat Prod Res 2010;12(8):691–695. 13. Zhai HY, Zhao C, Zhang N, Jin MN, Tang SA, Qin N, Kong DX, Duan HQ. Alkaloids from Pachysandra terminalis inhibit breast cancer invasion and have potential for development as antimetastasis therapeutic agents. J Nat Prod 2012;75(7):1305–1311. 14. Koduru S, Grierson DS, van de Venter M, Afolayan AJ. Anticancer activity of steroid alkaloids isolated from Solanum aculeastrum. Pharm Biol 2007;45(8):613–618. 15. Yan KH, Lee LM, Yan SH, Huang HC, Li CC, Lin HT, Chen PS. Tomatidine inhibits invasion of human lung adenocarcinoma cell A549 by reducing matrix metalloproteinases expression. Chem Biol Interact 2013;203(3):580–587. 16. Tang J, Li HL, Shen YH, Jin HZ, Yan SK, Liu RH, Zhang WD. Antitumor activity of extracts and compounds from the rhizomes of Veratrum dahuricum. Phytother Res 2008;22(8):1093– 1096. 17. Yan YX, Sun Y, Chen JC, Wang YY, Li Y, Qiu MH. Cytotoxic steroids from Sarcococca saligna. Planta Med 2011;77(15):1725–1729. 18. Sun Y, Yan YX, Chen JC, Lu L, Zhang XM, Li Y, Qiu MH. Pregnane alkaloids from Pachysandra axillaris. Steroids 2010;75(12):818–824. 19. Zha XM, Zhang FR, Shan JQ, Zhang YH, Liu JO, Sun HB. Synthesis and evaluation of in vitro anticancer activity of novel solasodine derivatives. Chin Chem Lett 2010;21(9):1087–1090. 20. Levitt RJ, Zhao Y, Blouin MJ, Pollak M. The hedgehog pathway inhibitor cyclopamine increases levels of p27, and decreases both expression of IGF-II and activation of Akt in PC-3 prostate cancer cells. Cancer Lett 2007;255(2):300–306. 21. Zhang JJ, Garrossian M, Gardner D, Garrossian A, Chang YT, Kim YK, Chang CWT. Synthesis and anticancer activity studies of cyclopamine derivatives. Bioorg Med Chem Lett 2008;18(4):1359– 1363. 22. Tang J, Li HL, Shen YH, Jin HZ, Yan SK, Liu RH, Zhang WD. Antitumor activity of extracts and compounds from the rhizomes of Veratrum dahuricum. Phytother Res 2008;22(8):1093–1096. 23. Steg A, Amm HM, Novak Z, Frost AR, Johnson MR. Gli3 mediates cell survival and sensitivity to cyclopamine in pancreatic cancer. Cancer Biol Ther 2010;10(9):897–906.

Medicinal Research Reviews DOI 10.1002/med

18

r JIANG ET AL.

24. Liang CH, Shiu LY, Chang LC, Sheu HM, Kuo KW. Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. Mol Nutr Food Res 2007;51(8):999–1005. 25. Qualtrough D, Buda A, Gaffield W, Williams AC, Paraskeva C. Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment. Int J Cancer 2004;110(6):831– 837. 26. Yue Y, Liu R, Liu J, Dong Q, Fan J. Experimental and theoretical investigation on the interaction between cyclovirobuxine D and human serum albumin. Spectrochim Acta A Mol Biomol Spectrosc 2014;128:552–558. 27. Lipinski RJ, Bushman W. Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening. Toxicol In Vitro 2010;24(5):1404–1409. 28. Funayama S, Noshita T, Shinoda K, Haga N, Nozoe S, Hayashi M, Komiyama K. Cytotoxic alkaloids of Pachysandra terminalis. Biol Pharm Bull 2000;23(2):262–264. 29. Welch KD, Panter KE, Lee ST, Gardner DR, Stegelmeier BL, Cook D. Cyclopamine-induced synophthalmia in sheep: Defining a critical window and toxicokinetic evaluation. J Appl Toxicol 2009;29(5):414–421. 30. de Medina P, Paillasse MR, Payre B, Silvente-Poirot S, Poirot M. Synthesis of new alkylaminooxysterols with potent cell differentiating activities: Identification of leads for the treatment of cancer and neurodegenerative diseases. J Med Chem 2009;52(23):7765–7777. 31. de Medina P, Paillasse MR, Segala G, Voisin M, Mhamdi L, Dalenc F, Lacroix-Triki M, Filleron T, Pont F, Al Saati T, Morisseau C, Hammock BD, Silvente-Poirot S, Poirot M. Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat Commun 2013;4:1840. 32. Aoki S, Watanabe Y, Tanabe D, Setiawan A, Arai M, Kobayashi M. Cortistatins J, K, L, novel abeo9(10–19)-androstane-type steroidal alkaloids with isoquinoline unit, from marine sponge Corticium simplex. Tetrahedron Lett 2007;48(26):4485–4488. 33. Aoki S, Watanabe Y, Sanagawa M, Setiawan A, Kotoku N, Kobayashi M. Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex. J Am Chem Soc 2006;128(10):3148–3149. 34. Watanabe Y, Aoki S, Tanabe D, Setiawan A, Kobayashi M. Cortistatins E, F, G, and H, four novel steroidal alkaloids from marine sponge Corticium simplex. Tetrahedron 2007;63(19):4074–4079. 35. Aoki S, Watanabe Y, Tanabe D, Arai M, Suna H, Miyamoto K, Tsujibo H, Tsujikawa K, Yamamoto H, Kobayashi M. Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids. Bioorg Med Chem 2007;15(21):6758–6762. 36. Lu J, Sun D, Gao S, Gao Y, Ye J, Liu P. Cyclovirobuxine D induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells. J Pharmacol Sci 2014;125(1):74– 82. 37. Nikolic NC, Stankovic MZ, Markovic DZ. Liquid-liquid systems for acid hydrolysis of glycoalkaloids from Solanum tuberosum L. tuber sprouts and solanidine extraction. Med Sci Monit 2005;11(7):200–205. 38. Yamashoji S, Matsuda T. Synergistic cytotoxicity induced by alpha-solanine and alpha-chaconine. Food Chem 2013;141(2):669–674. 39. Lee K-R, Kozukue N, Han J-S, Park J-H, Chang E-y, Baek E-J, Chang J-S, Friedman M. Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. J Agric Food Chem 2004;52(10):2832–2839. 40. Friedman M, Lee KR, Kim HJ, Lee IS, Kozukue N. Anticarcinogenic effects of glycoalkaloids from potatoes against human cervical, liver, lymphoma, and stomach cancer cells. J Agric Food Chem 2005;53(15):6162–6169. 41. Lu MK, Shih YW, Chang Chien TT, Fang LH, Huang HC, Chen PS. Alpha-solanine inhibits human melanoma cell migration and invasion by reducing matrix metalloproteinase-2/9 activities. Biol Pharm Bull 2010;33(10):1685–1691. Medicinal Research Reviews DOI 10.1002/med

THERAPEUTIC POTENTIAL OF STEROIDAL ALKALOIDS

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42. Lu MK, Chen PH, Shih YW, Chang YT, Huang ET, Liu CR, Chen PS. Alpha-chaconine inhibits angiogenesis in vitro by reducing matrix metalloproteinase-2. Biol Pharm Bull 2010;33(4):622–630. 43. Shih YW, Chen PS, Wu CH, Jeng YF, Wang CJ. Alpha-chaconine-reduced metastasis involves a PI3K/Akt signaling pathway with downregulation of NF-kappaB in human lung adenocarcinoma A549 cells. J Agric Food Chem 2007;55(26):11035–11043. 44. Zupko I, Molnar J, Rethy B, Minorics R, Frank E, Wolfling J, Molnar J, Ocsovszki I, Topcu Z, Bito T, Puskas LG. Anticancer and multidrug resistance-reversal effects of solanidine analogs synthetized from pregnadienolone acetate. Molecules 2014;19(2):2061–2076. 45. Lv C, Kong H, Dong G, Liu L, Tong K, Sun H, Chen B, Zhang C, Zhou M. Antitumor efficacy of alpha-solanine against pancreatic cancer in vitro and in vivo. PLoS One 2014;9(2):e87868. 46. Mohsenikia M, Alizadeh AM, Khodayari S, Khodayari H, Kouhpayeh SA, Karimi A, Zamani M, Azizian S, Mohagheghi MA. The protective and therapeutic effects of alpha-solanine on mice breast cancer. Euro J Pharmacol 2013;718(1–3):1–9. 47. Shen KH, Liao AC, Hung JH, Lee WJ, Hu KC, Lin PT, Liao RF, Chen PS. Alpha-solanine inhibits invasion of human prostate cancer cell by suppressing epithelial-mesenchymal transition and MMPs expression. Molecules 2014;19(8):11896–11914. 48. Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Onco 2006;18(1):77–82. 49. Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T. Regulation of matrix metalloproteinases: An overview. Mol Cell Biochem 2003;253(1–2):269–285. 50. Yang SA, Paek SH, Kozukue N, Lee KR, Kim JA. Alpha-chaconine, a potato glycoalkaloid, induces apoptosis of HT-29 human colon cancer cells through caspase-3 activation and inhibition of ERK 1/2 phosphorylation. Food Chem Toxicol 2006;44(6):839–846. 51. Patel K, Singh RB, Patel DK. Medicinal significance, pharmacological activities, and analytical aspects of solasodine: A concise report of current scientific literature. J Acute Dis 2013;2(2):92–98. 52. Cham B. Solasodine glycosides as anti-cancer agents: Pre-clinical and clinical studies. Asia Pac J Pharmacol 1994;9(2):113–118. 53. Cham BE, Gilliver M, Wilson L. Antitumour effects of glycoalkaloids isolated from Solanum sodomaeum. Planta Med 1987;53(1):34–36. 54. Wei G, Wang J, Du Y. Total synthesis of solamargine. Bioorg Med Chem Lett 2011;21(10):2930– 2933. 55. Ding X, Zhu F, Yang Y, Li M. Purification, antitumor activity in vitro of steroidal glycoalkaloids from black nightshade (Solanum nigrum L.). Food Chem 2013;141(2):1181–1186. 56. Ding X, Zhu F, Gao S. Purification, antitumour and immunomodulatory activity of waterextractable and alkali-extractable polysaccharides from Solanum nigrum L. Food Chem 2012;131(2):677–684. 57. Munari CC, de Oliveira PF, Campos JC, Martins SD, Da Costa JC, Bastos JK, Tavares DC. Antiproliferative activity of Solanum lycocarpum alkaloidic extract and their constituents, solamargine and solasonine, in tumor cell lines. J Nat Med 2013;68(1):234–241. 58. Liu LF, Liang CH, Shiu LY, Lin WL, Lin CC, Kuo KW. Action of solamargine on human lung cancer cells—Enhancement of the susceptibility of cancer cells to TNFs. FEBS Lett 2004;577(1– 2):67–74. 59. Ikeda T, Tsumagari H, Honbu T, Nohara T. Cytotoxic activity of steroidal glycosides from solanum plants. Biol Pharm Bull 2003;26(8):1198–1201. 60. Ono M, Nishimura K, Suzuki K, Fukushima T, Igoshi K, Yoshimitsu H, Ikeda T, Nohara T. Steroidal glycosides from the underground parts of Solanum sodomaeum. Chem Pharm Bull 2006;54(2):230–233. 61. Shiu LY, Chang LC, Liang CH, Huang YS, Sheu HM, Kuo KW. Solamargine induces apoptosis and sensitizes breast cancer cells to cisplatin. Food Chem Toxicol 2007;45(11):2155–2164. 62. Ai JX. The role of SBHL in tumor growth and immune functions in mice. International Conference on Human Health and Biomedical Engineering—HHBE 2011 Jilin, China. p 521–523. Medicinal Research Reviews DOI 10.1002/med

20

r JIANG ET AL.

63. Ai JX. The experimental investigation of SBHL on reversing acquired multi-drug resistance on S180 mouse tumor bearing model. International Conference on Human Health and Biomedical Engineering—HHBE 2011 Jilin, China. p 518–520. 64. Tang Z, Zhang Y, Li N, Xu L, Zhao B, Xiao W, Wang Z, Bi Y. Extraction, purification technology and antineoplastic effects of solamargine. Zhongguo Zhong Yao Za Zhi 2011;36(16):2192–2195. 65. Cham BE. Cancer intralesion chemotherapy with solasodine rhamnosyl glycosides. Res J Biol Sci 2008;3(9):1008–1017. 66. Cham BE. Solasodine rhamnosyl glycosides in a cream formulation is effective for treating large and troublesome skin cancers. Res J Biol Sci 2007;2(7):749–761. 67. Schramm EC, Nelson SK, Steber CM. Wheat ABA-insensitive mutants result in reduced grain dormancy. Euphytica 2012;188(1):35–49. 68. Cham BE. Topical CuradermBEC5 therapy for periocular nonmela-noma skin cancers: A review of clinical outcomes. Int J Clin Med 2013;4(5):233–238. 69. Punjabi S, Cook LJ, Kersey P, Marks R, Cerio R. Solasodine glycoalkaloids: A novel topical therapy for basal cell carcinoma. A double-blind, randomized, placebo-controlled, parallel group, multicenter study. Int J Dermatol 2008;47(1):78–82. 70. Lipinski RJ, Song C, Sulik KK, Everson JL, Gipp JJ, Yan D, Bushman W, Rowland IJ. Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications. Birth Defects Res A Clin Mol Teratol 2010;88(4):232–240. 71. Fisher DE. Apoptosis in cancer therapy: Crossing the threshold. Cell 1994;78(4):539–542. 72. Trouillas P, Corbiere C, Liagre B, Duroux JL, Beneytout JL. Structure-function relationship for saponin effects on cell cycle arrest and apoptosis in the human 1547 osteosarcoma cells: A molecular modelling approach of natural molecules structurally close to diosgenin. Bioorg Med Chem 2005;13(4):1141–1149. 73. Hsu SH, Tsai TR, Lin CN, Yen MH, Kuo KW. Solamargine purified from Solanum incanum Chinese herb triggers gene expression of human TNFR I which may lead to cell apoptosis. Biochem Biophys Res Commun 1996;229(1):1–5. 74. Ding X, Zhu FS, Li M, Gao SG. Induction of apoptosis in human hepatoma SMMC-7721 cells by solamargine from Solanum nigrum L. J Ethnopharmacol 2012;139(2):599–604. 75. Sun LM, Zhao Y, Li X, Yuan HQ, Cheng AX, Lou HX. A lysosomal-mitochondrial death pathway is induced by solamargine in human K562 leukemia cells. Toxicol In Vitro 2010;24(6):1504–1511. 76. Li X, Zhao Y, Wu WK, Liu S, Cui M, Lou H. Solamargine induces apoptosis associated with p53 transcription-dependent and transcription-independent pathways in human osteosarcoma U2OS cells. Life Sci 2011;88(7–8):314–321. 77. Li X, Zhao Y, Ji M, Liu S, Cui M, Lou H. Induction of actin disruption and downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. Mol Nutr Res 2011;51:999–1005. 78. Friedman M. Tomato glycoalkaloids: Role in the plant and in the diet. J Agric Food Chem 2002;50(21):5751–5780. 79. Friedman M, Levin CE, Lee SU, Kim HJ, Lee IS, Byun JO, Kozukue N. Tomatine-containing green tomato extracts inhibit growth of human breast, colon, liver, and stomach cancer cells. J Agric Food Chem 2009;57(13):5727–5733. 80. Choi SH, Ahn JB, Kozukue N, Kim HJ, Nishitani Y, Zhang L, Mizuno M, Levin CE, Friedman M. Structure–activity relationships of α-, β1-, γ -, and δ-tomatine and tomatidine against human breast (MDA-MB-231), gastric (KATO-III), and prostate (PC3) cancer cells. J Agric Food Chem 2012;60(15):3891–3899. 81. Chiang CT, Way TD, Tsai SJ, Lin JK. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett 2007;581(30):5735–5742. 82. Lavie Y, Harel-Orbital T, Gaffield W, Liscovitch M. Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human cancer cells. Anticancer Res 2001;21(2A):1189–1194. Medicinal Research Reviews DOI 10.1002/med

THERAPEUTIC POTENTIAL OF STEROIDAL ALKALOIDS

r 21

83. Chao MW, Chen CH, Chang YL, Teng CM, Pan SL. α-Tomatine-mediated anti-cancer activity in vitro and in vivo through cell cycle-and caspase-independent pathways. PLoS One 2012;7(9):44093. 84. Shieh JM, Cheng TH, Shi MD, Wu PF, Chen Y, Ko SC, Shih YW. α-Tomatine suppresses invasion and migration of human non-small cell lung cancer NCI-H460 cells through inactivating FAK/PI3K/Akt signaling pathway and reducing binding activity of NF-κB. Cell Biochem Biophys 2011;60(3):297–310. 85. Lee ST, Wong PF, Cheah SC, Mustafa MR. Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells. PLoS One 2011;6(4):e18915. 86. Keeler RF. Teratogenic compounds of Veratrum californicum (Durand) X. Cyclopia in rabbits produced by cyclopamine. Teratology 1970;3(2):175–180. 87. Cooper MK, Porter JA, Young KE, Beachy PA. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 1998;280(5369):1603–1607. 88. Khanfar MA, El Sayed KA. The Veratrum alkaloids jervine, veratramine, and their analogues as prostate cancer migration and proliferation inhibitors: Biological evaluation and pharmacophore modeling. Med Chem Res 2013;22(10):4775–4786. 89. Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002;297(5586):1559–1561. 90. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997;389(6653):876–881. 91. Watkins DN, Berman DM, Burkholder SG, Wang BL, Beachy PA, Baylin SB. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003;422(6929):313–317. 92. Nishimaki H, Kasai K, Kozaki K, Takeo T, Ikeda H, Saga S, Nitta M, Itoh G. A role of activated Sonic hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun 2004;314(2):313–320. 93. Zhang X, Harrington N, Moraes RC, Wu MF, Hilsenbeck SG, Lewis MT. Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast Cancer Res Treat 2009;115(3):505–521. 94. Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431(7009):707–712. 95. Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: A new paradigm for combination therapy in solid cancers. Cancer Res 2007;67(5):2187–2196. 96. Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425(6960):846–851. 97. Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S. Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res 2009;29(11):4629– 4632. 98. Ghezali L, Leger DY, Limami Y, Cook-Moreau J, Beneytout JL, Liagre B. Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect. Exp Cell Res 2013;319(7):1043–1053. 99. Chen XL, Cheng QY, She MR, Wang QA, Huang XH, Cao LQ, Fu XH, Chen JS. Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. Arch Med Res 2010;41(5):315–323. 100. Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, Ruiz i Altaba A. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci USA 2004;101(34):12561–12566. Medicinal Research Reviews DOI 10.1002/med

22

r JIANG ET AL.

101. Gerber AN, Wilson CW, Li YJ, Chuang PT. The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation. Oncogene 2007;26(8):1122–1136. 102. Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: Tumours, embryos and stem cells. Nat Rev Cancer 2002;2(5):361–372. 103. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003;3(12):903–911. 104. Bian YH, Huang SH, Yang L, Ma XL, Xie JW, Zhang HW. Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World J Gastroenterol 2007;13(11):1659–1665. 105. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000;406(6799):1005–1009. 106. Giannis A, Heretsch P, Sarli V, Stossel A. Synthesis of cyclopamine using a biomimetic and diastereoselective approach. Angew Chem Int Ed Engl 2009;48(42):7911–7914. 107. Heretsch P, Buttner A, Tzagkaroulaki L, Zahn S, Kirchner B, Giannis A. Exo-cyclopamine—A stable and potent inhibitor of hedgehog-signaling. Chem Commun 2011;47(26):7362–7364. 108. Incardona JP, Gaffield W, Lange Y, Cooney A, Pentchev PG, Liu S, Watson JA, Kapur RP, Roelink H. Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport. Dev Biol 2000;224(2):440–452. 109. Rahman A, Anjum S, Farooq A, Khan MR, Parveen Z, Choudhary MI. Antibacterial steroidal alkaloids from Sarcococca saligna. J Nat Prod 1998;61(2):202–206. 110. Mitchell G, Lafrance M, Boulanger S, Seguin DL, Guay I, Gattuso M, Marsault E, Bouarab K, Malouin F. Tomatidine acts in synergy with aminoglycoside antibiotics against multiresistant Staphylococcus aureus and prevents virulence gene expression. J Antimicrob Chemother 2012;67(3):559–568. 111. Zhou CX, Liu JY, Ye WC, Liu CH, Tan RX. Neoverataline A and B, two antifungal alkaloids with a novel carbon skeleton from Veratrum taliense. Tetrahedron 2003;59(30):5743–5747. 112. Ito S, Ihara T, Tamura H, Tanaka S, Ikeda T, Kajihara H, Dissanayake C, Abdel-Motaal FF, El-Sayed MA. Alpha-tomatine, the major saponin in tomato, induces programmed cell death mediated by reactive oxygen species in the fungal pathogen Fusarium oxysporum. FEBS Lett 2007;581(17):3217–3222. 113. Devkota KP, Lenta BN, Choudhary MI, Naz Q, Fekam FB, Rosenthal PJ, Sewald N. Cholinesterase inhibiting and antiplasmodial steroidal alkaloids from Sarcococca hookeriana. Chem Pharm Bull 2007;55(9):1397–1401. 114. Devkota KP, Lenta BN, Wansi JD, Choudhary MI, Kisangau DP, Naz Q, Samreen, Sewald N. Bioactive 5alpha-pregnane-type steroidal alkaloids from Sarcococca hookeriana. J Nat Prod 2008;71(8):1481–1484. 115. Mousseau G, Clementz MA, Bakeman WN, Nagarsheth N, Cameron M, Shi J, Baran P, Fromentin R, Chomont N, Valente ST. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe 2012;12(1):97–108. 116. Kenny OM, McCarthy CM, Brunton NP, Hossain MB, Rai DK, Collins SG, Jones PW, Maguire AR, O’Brien NM. Anti-inflammatory properties of potato glycoalkaloids in stimulated Jurkat and Raw 264.7 mouse macrophages. Life Sci 2013;92(13):775–782. 117. Chiu FL, Lin JK. Tomatidine inhibits iNOS and COX-2 through suppression of NF-kappaB and JNK pathways in LPS-stimulated mouse macrophages. FEBS Lett 2008;582(16):2407–2412. 118. Chang LC, Bhat KP, Pisha E, Kennelly EJ, Fong HH, Pezzuto JM, Kinghorn AD. Activity-guided isolation of steroidal alkaloid antiestrogen-binding site inhibitors from Pachysandra procumbens. J Nat Prod 1998;61(10):1257–1262. 119. Chang LC, Bhat KPL, Fong HHS, Pezzuto JM, Kinghorn AD. Novel bioactive steroidal alkaloids from Pachysandra procumbens. Tetrahedron 2000;56(20):3133–3138. 120. Gupta RS, Dixit VP. Effects of short-term treatment of solasodine on cauda epididymis in dogs. Indian J Exp Biol 2002;40(2):169–173. Medicinal Research Reviews DOI 10.1002/med

THERAPEUTIC POTENTIAL OF STEROIDAL ALKALOIDS

r 23

121. Wang YX, Zheng YM, Tan YH, Sheng BH. [Anti-atrial fibrillation effects of cyclovirobuxine-D and its electrophysiological mechanism studied on guinea pig atria]. Yao Xue Xue Bao 1996;31(7):481– 486. 122. Chen QW, Shan HL, Sun HL, Wang H, Yang BF. [Effects of cyclovirobuxine D on intracellular Ca2+ and L-type Ca2+ current in rat ventricular cardiomyocytes]. Yao Xue Xue Bao 2004;39(7):500–503. 123. Vacca G, Battaglia A, Brunelleschi S, Grossini E, Mary DA, Molinari C, Viano I. Hemodynamic effects of the intravenous administration of cyclovirobuxine D [correction of cyclorirobuxine D] in anesthetized pigs. Life Sci 1997;61(17):255–261. 124. Deng L, Huang H, Xu MX, Zhou SQ, Wang XW, Lu M, Ren F, Li DQ. [Structural modification and bioactivity of cyclovirobuxine D]. Yao Xue Xue Bao 2004;39(6):434–438. 125. Hu D, Liu X, Wang Y, Chen S. Cyclovirobuxine D ameliorates acute myocardial ischemia by K(ATP) channel opening, nitric oxide release and anti-thrombosis. Euro J Pharmacol 2007;569(1– 2):103–109. 126. Chen ZQ, Hu SJ, Shi WY, Du J, Shen Y, Xia Q. [Electrophysiologic study of the biphasic effects of cyclovirobuxine D on arrhythmias]. Zhongguo Zhong Xi Yi Jie He Za Zhi 2004;24(11):1010–1013. 127. Yu B, Fang TH, Lu GH, Xu HQ, Lu JF. Beneficial effect of cyclovirobuxine D on heart failure rats following myocardial infarction. Fitoterapia 2011;82(6):868–877. 128. Gaffield W. The Veratrum alkaloids: Natural tools for studying embryonic development. Studies in Natural Products Chemistry. Elsevier B. V, Philadelphia; 2000. p 563–589. 129. Keeler RF. Teratogenic effects of cyclopamine and jervine in rats, mice and hamsters. Proc Soc Exp Biol Med 1975;149(1):302–306. 130. Keeler RF, Young S, Brown D. Spina bifida, exencephaly, and cranial bleb produced in hamsters by the solanum alkaloid solasodine. Res Commun Chem Pathol Pharmacol 1976;13(4):723–730. 131. Friedman M, Rayburn JR, Bantle JA. Developmental toxicology of potato alkaloids in the frog embryo teratogenesis assay–Xenopus (FETAX). Food Chem Toxicol 1991;29(8):537–547. 132. Chaube S, Swinyard CA. Teratological and toxicological studies of alkaloidal and phenolic compounds from Solanum tuberosum L. Toxicol Appl Pharmacol 1976;36(2):227–237. 133. Smith DB, Roddick JG, Jones JL. Potato glycoalkaloids: Some unanswered questions. Trends Food Sci Technol 1996;7(4):126–131. 134. Langkilde S, Schroder M, Stewart D, Meyer O, Conner S, Davies H, Poulsen M. Acute toxicity of high doses of the glycoalkaloids, alpha-solanine and alpha-chaconine, in the Syrian Golden hamster. J Agric Food Chem 2008;56(18):8753–8760. 135. Friedman M, Henika PR, Mackey BE. Effect of feeding solanidine, solasodine and tomatidine to non-pregnant and pregnant mice. Food Chem Toxicol 2003;41(1):61–71. 136. Atta ur R, Feroz F, Naeem I, Zaheer ul H, Nawaz SA, Khan N, Khan MR, Choudhary MI. New pregnane-type steroidal alkaloids from Sarcocca saligna and their cholinesterase inhibitory activity. Steroids 2004;69(11–12):735–741. 137. Roddick JG. The acetylcholinesterase-inhibitory activity of steroidal glycoalkaloids and their aglycones. Phytochemistry 1989;28(10):2631–2634. 138. Khalid A, Zaheer ul H, Anjum S, Khan MR, Atta ur R, Choudhary MI. Kinetics and structureactivity relationship studies on pregnane-type steroidal alkaloids that inhibit cholinesterases. Bioorg Med Chem 2004;12(9):1995–2003. 139. Gilani AH, Aftab K, Saeed S, Ali RA, Rahman A-u. O-acetyljervine: A new β-adrenoceptor agonist from Veratrum album. Arch Pharm Res 1995;18(2):129–132. 140. Tang J, Li HL, Shen YH, Jin HZ, Yan SK, Liu XH, Zeng HW, Liu RH, Tan YX, Zhang WD. Antitumor and antiplatelet activity of alkaloids from Veratrum dahuricum. Phytother Res 2010;24(6):821– 826. 141. Zhang YH, Ruan HL, Pi HF, Cai JY, Zeng FB, Zhao W, Wu JZ. Hubei Fritillaria alkaloid monomer antitussive, expectorant and antiasthmatic effects. Chin Herb Med 2005;36(8):1026.

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r JIANG ET AL.

142. Vieira PM, Marinho LP, Ferri SC, Chen-Chen L. Protective effects of steroidal alkaloids isolated from Solanum paniculatum L. against mitomycin cytotoxic and genotoxic actions. An Acad Bras Cienc 2013;85(2):553–560.

Qi-Wei Jiang is a graduate student at Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, China. His work focuses on development of anticancer agents from natural products and investigation of molecular mechanisms. Mei-Wan Chen received her PhD from Sun Yat-Sen University, China and was a visiting scholar from 2009 to 2010 at University of Mississippi. At present, she is an Assistant Professor at Institute of Chinese Medical Sciences, University of Macau and specializes in drug-delivery systems (DDS) and druggability evaluation for Chinese medicine, and targeted DDS for cancer treatment. She has more than 40 papers published in SCI journals so far. Ke-Jun Cheng received his PhD in Medicinal Chemistry from Fudan University, Shanghai. He then joined the research group of Prof. Haian Fu at Emory University as a postdoctoral fellow and worked on chemical biological study of natural products, mainly on the high-throughput and high-content screening (HTS/HCS) and protein–protein interactions study of anticancer bioactive compounds. He began his independent career at Lishui Institute of Agricultural Sciences in 2012 and currently is an Associate Professor and Director of Chemical Biology Center. Research interests in the Cheng Group are at the interface of chemistry and biology focused on isolation, chemical identification, chemical derivatization, and cellular mechanism of action studies of bioactive natural products. Pei-Zhong Yu is an Associate Professor at School of Pharmacy, Fudan University. He received his PhD degree in pharmacy from Fudan University. He has published over 30 papers in the peer-reviewed journals, such as J Nat Prod, Phytochem, etc. His research is focused on (1) the isolation and separation of natural active constitutes from medicinal plants, especially in anticancer and antivirus activities; (2) molecular structure identification and structure–activity relationship study. Xing Wei received his PhD from University of Minnesota, and finished 4-year postdoctoral fellow at Yale University. He worked as an investigator in Biogen Idec and Geron, USA, and a Professor at Shantou University, China. From January 2010, he was appointed as a Professor at Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, China. He published over 40 SCI papers in prestigious international journals, including Nature Biotech, J Exp Med, PNAS, Nucleic Acids Res, etc. His work was supported by two grants from National Natural Science Foundation of China and others. He was invited as section chairman at many international conferences and reviewer for over 10 international SCI journals. His research projects include (1) cancer stem cells and development of monoclonal antibodies for treatment of cancer. (2) Human mesenchymal stem cell growth and differentiation and molecular mechanisms, and their use for treatment of liver, pancreas, and skin diseases. Zhi Shi received his PhD from Prof. Li-Wu Fu’s lab at Cancer Center of Sun Yat-sen University, China, and was a 1-year visiting scholar at Prof. Zhe-Sheng Chen’s lab of Saint John’s University as well as 4-year postdoctoral fellow at Prof. Haian Fu’s lab of Emory University. From June Medicinal Research Reviews DOI 10.1002/med

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2012, he was appointed as a Professor at Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, China. He published over 30 SCI papers in the peer-reviewed journals, such as Cancer Res, Oncogene, Biotechnology Advances, Drug Disc Today, etc. His work was supported by grants from National Natural Science Foundation of China, Guangdong Natural Science Funds for Distinguished Young Scholar, and others. He was honored with four awards including the first prize of the Science and Technology Award of Chinese Anticancer Association, and was also invited as reviewer for over 10 peer-reviewed journals. His research focus on (1) investigating the mechanism of tumorigenesis including the signaling pathways and protein–protein interaction network in cancers; (2) developing the new anticancer drugs including small compounds, peptides, recombinant proteins, antibodies, etc.

Medicinal Research Reviews DOI 10.1002/med

Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases.

Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recen...
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