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Expert Opinion on Therapeutic Patents

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Erratum To cite this article: (2015) Erratum, Expert Opinion on Therapeutic Patents, 25:6, 737-737, DOI: 10.1517/13543776.2015.1042242 To link to this article: http://dx.doi.org/10.1517/13543776.2015.1042242

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Date: 05 November 2015, At: 13:07

1.

Introduction

2.

Identification of CSCs

3.

The challenge of treatment of CSCs

Natural product-based therapeutics for the treatment of cancer stem cells: a patent review (2010 -- 2013) Chien-Hsing Lee & Chung-Yi Chen† †

5.

Expert opinion

Fooyin University, School of Medical and Health Sciences, Department of Medical Laboratory Science and Biotechnology, Kaohsiung, Taiwan

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Effects of natural products on CSCs

Introduction: Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess numerous intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs and radiation therapy, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. This review presents the up-to-date natural product-based therapeutics for the treatment of CSCs. Areas covered: This review gives an account of the recent therapeutic patent literature (2010 -- 2013) describing the applications of natural products on CSCs. In this review, many of the therapeutic applications of natural products reported in international patents have been discussed. In addition to selected biological data, some of pharmaceutical applications are also summarized. Because of the large number of patents registered in this period relative to natural products the attention was focused, in this first part of the review, on inhibitors of six cancers. Expert opinion: This patent review aims to highlight the use of natural products to treat cancer by targeting CSCs. Most of the described products are shown to have beneficial therapeutic effects and their uses for developing new formulations.

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Keywords: biomarkers, cancer stem cells, CD133, CD44, natural products Expert Opin. Ther. Patents [Early Online]

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Expert Opin. Ther. Patents Downloaded fromby ashley-prod.literatumonline.com by IBI Downloaded [220.180.94.122] at 13:07 05 Circulation November- Ashley 2015 Publications Ltd on 10/05/15 For personal use only.

Review

1.

Introduction

Cancer is estimated to be the leading cause of death worldwide by WHO. Tumorigenesis occurs when normal cells accumulate sufficient mutations to allow for sustained proliferation, evasion of apoptosis and ultimately tissue invasion and metastasis [1]. Substantial progress has been made with respect to the treatment of primary tumors using surgery, chemotherapy and radiation therapy. However, the advancement of cancer to an invasive or metastatic stage is frequently associated with a poor patient prognosis and remains a critical hurdle in the treatment of the disease [2]. Advances in acute myeloid leukemia (AML) ultimately led to the discovery of AML cancer stem cells (CSCs) in 1994 by John Dick’s group [3]. The hierarchical CSC model proposes only a small fraction (0.5 -- 10%) of cells within the cancer, known as CSCs, and are capable of tumor initiation and unlimited self-renewal through asymmetric division [4,5]. Due to their extraordinary characteristics, CSCs are thought to be the basis for tumor initiation, development, metastasis and recurrence. The ability to self-renew allows the expansion of the CSC pool, in response to controlled or uncontrolled

10.1517/13543776.2015.1021688 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

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C. -H. Lee & C. -Y. Chen

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This box summarizes key points contained in the article.

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systemic and local signals, respectively [6]. Actually differentiation from the CSC compartment involves a sequential production of cells with more and more tissue-specific specialization [7]. In addition, recent studies indicate that CSCs may be responsible for tumor relapse and resistance to therapy [8]. These properties of CSCs are thought to cause cancer treatment failure, relapse and drug resistance [9]. Below, novel therapeutic developments related to natural products are briefly described. For the literature search, the particular aim of this review is to summarize selected patents published from 2010 -- 2013 and describe the direction of natural products applications in treatment of CSCs, which is the incidence and mortality rates for the major cancer in Taiwan.

Identification of CSCs

No universal CSC markers exist; rather, CSC markers are likely tumor and/or phenotype specific, and require biological validation for the predicted phenotype. Therefore, CSCs contain distinct cell-specific markers that distinguish them from non-CSC populations. Distinct and specific surface biomarker phenotypes can be used to distinguish CSCs from other tumor cells and normal stem cells. Currently, the most common method used to identify CSCs is fluorescence-activated cell sorting based on cell surface markers or intracellular molecules. A variety of different cellular markers have been proposed to differentiate between CSCs and the general population of cancer cells within a tumor (Figure 1) [10,11]. Putative markers of high relevance include the glycosylated isoform of CD133/prominin-1 [12]. Another marker, first described as CSC marker in breast cancer [13], is the hyaluronic acid binding receptor CD44, which controls cell--cell interactions and is involved in cross-talk between CSCs and their microenvironment [14]. In addition, other markers as candidate CSC biomarkers include the following: the expression of ATP-binding cassette (ABC) drug pumps, such as ABC sub-family G member 2 (ABCG2)/breast cancer resistance protein and P-glycoprotein/multidrug resistance protein 1 [15,16], activation of the Hedgehog, Notch and Wnt/b-catenin signaling [17], the Akt/PKB and ATR/CHK1 survival pathways [18], aberrant

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Natural products such are gaining importance as attractive adjuvant anti-cancer agents with practically minimal or no side effects. Natural products also improve the efficacy of chemoand radiotherapy, making them ideal partners for combination therapy regimens. Natural products may represent a powerful strategy for eradicating CSCs in cancer patients.

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PI3K/Akt/mTOR-mediated signaling and loss of phosphatase and tensin homolog (PTEN) [19,20], amplified aldehyde dehydrogenase 1 (ALDH1) activation [21], the activity of checkpoint and efficient DNA and oxidative damage repair [22,23], acquisition of epithelial mesenchymal transition [24], constitutive activation of NF-kB [25] and general radioresistance [26,27], protection from apoptosis by autocrine production of IL-4 [28], various mechanisms of apoptosis resistance and defective apoptotic signaling [29], protection by microenvironment and niche networks [30,31], metabolic alterations with a preference for hypoxia [32] and immune evasion [33]. Side population (SP) cells have been characterized as a subset of cells exhibiting CSC properties with a distinctly low Hoechst 33342 dye exclusion in flow cytometry, especially when molecular markers for stem cells are unknown [34]. SP cells have been isolated from various solid tumors that have been shown to overexpress candidate stem cell markers possessing the capacity to self renew, and give rise to differentiated cells in vitro and in vivo [35,36]. The efflux of the Hoechst dye depends upon the expression of the ABC superfamily of membrane transporters, which has a specific ABC domain that allows for ATP binding and hydrolysis [37,38]. SP cells have been shown to possess abnormal activation of Wnt/b-catenin signaling indicating that SP cells may be a trigger for tumor cell proliferation and metastasis [5]. Similar to conventional anticancer drugs, numerous novel tumor-targeted drugs were designed to target rapidly proliferating cancer cells, so that CSCs might be relatively insensitive to these drugs. For instance, imatinib has been shown to eliminate proliferating, committed leukemia progenitors, but not non-proliferating chronic myeloid leukemia stem cells [39]. Furthermore, trastuzumab monotherapy in patients with HER2-overexpressing metastatic breast cancer shows a low response rate, and primary or acquired resistance to trastuzumab occurs frequently in different clinical settings even when combination regimes are used [40]. One important mechanism of trastuzumab resistance in the therapy of HER2-overexpressing breast cancer might be CSCs displaying aberrant PI3K signaling and loss of PTEN [20]. Sorafenib fails to eradicate AML stem and primitive progenitor cells due to robust protection of these cells by the bone marrow stromal microenvironment, providing a further paradigm that novel tumor-targeted drugs fail to eliminate CSCs [41]. Therefore, the heterogeneity, the interaction with the microenvironment, the origin and the genetic background can affect the biological properties, the plasticity and the phenotype of CSCs.

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Article highlights.

3.

The challenge of treatment of CSCs

If CSCs are the ‘roots’ of cancer, these are the cells that must be specifically eliminated for a successful therapy. However, CSC is resistant to chemo- and radiation therapy, often leading to the failure of conventional therapy and resulting relapse. Frequent cancer recurrence may be due to the preferential killing of differentiated cells while leaving CSCs

Expert Opin. Ther. Patents (2015) 25(6)

Natural product-based therapeutics for the treatment of cancer stem cells: a patent review (2010 -- 2013)

Colon

Liver

Lung

Breast

Prostate

Melanoma

Ovarian

CD24 CD26 CD29 CD44 CD133 CD166

CD13 CD24 CD44 CD90 CD133

CD90 CD117 CD133

CD24 CD44 CD90 CD133

CD44 CD133 CD166

CD20 CD133 CD271

CD24 CD44 CD117 CD133

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Figure 1. Cell surface marker of CSCs. A summary of CSC surface markers identified in a variety of cancer types. CSCs: Cancer stem cells.

Chemotherapy

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Radiation

CSC resistance

DNA damage

• Overexpression of checkpoint kinases 1/2 (Chk 1/2)

Drug infiltration

Apoptosis

Microenvironment

• Overexpression of • Altered balance of multidrug-resistance signaling with transporters FLT3/Akt/Bcl

• Hypoxic niches

Other • Slowed cell cycle kinetics

Figure 2. Schematic diagram of the mechanisms leading to CSC resistance to chemo- and radiation therapy. CSCs have been found to exhibit a number of genetic and cellular adaptations that confer resistance to classical therapeutic approaches, including slow cell cycle kinetics, efficient DNA repair, high expression of multidrug resistance-type membrane transporters, resistance to apoptosis and protection by a hypoxic niche environment. CSCs: Cancer stem cells.

behind. A better understanding of the mechanisms underlying CSCs resistance to treatment is necessary and may provide a more effective therapy to overcome the resistance. It is well known that many cancers are resistant to currently available therapies such as radiotherapy, which could be due to factors such as the presence of proliferatively quiescent CSCs and because the CSCs may be located within hypoxic niches [26]. In addition, a number of genetic and cellular adaptations have been found to confer resistance to classical therapeutic approaches, such as relative dormancy/slow cell cycle kinetics, efficient DNA repair, the expression of multidrug-resistance transporters and resistance to apoptosis (Figure 2) [11]. One potential modulator of CSC resistance to DNA targeting agents is the family of checkpoint kinases 1/2 which have higher activities in CSCs than in non-stem cells [42]. CSCs may also derive resistance to chemical mutagens through the expression of drug efflux pumps such as the ABC family that can transport the drugs out of cells. The activation of the Akt pathway and the over-amplification

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CSC markers for distinct solid tumour types

of apoptosis inhibitor proteins might also be conferred to CSCs resistance (Figure 2). Drug resistance also means that specific therapies can actually enrich for CSCs in the residual tumor [43]. In such cases, therapies must be developed to bypass this resistance in CSCs.

4.

Effects of natural products on CSCs

Understanding the mechanisms that regulate self-renewal of CSCs and the points at which there is potential for intervention by natural products is of greatest importance in the discovery of anticancer drugs targeting CSCs (Figure 3 and Table 1). Colon cancer Honokiol is a biphenolic compound from Magnolia officianalis that is used in traditional Chinese and Japanese medicine for antithrombotic, antitumor activities and the treatment of various ailments including ulcer, allergy and bacterial 4.1


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Figure 3. Natural products with demonstrated efficacy toward modulating targets critical to CSCs. CSCs: Cancer stem cells.

infections [44-46]. CSCs are implicated in resistance to ionizing radiation (IR) and chemotherapy [47]. A recent study has shown that the combination of honokiol and IR reduced expression of CSC marker protein DCLK1 [44]. In addition, 4

honokiol reduced levels of activated Notch-1, its ligand Jagged-1 and the downstream target gene Hes-1. Therefore, honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the g-secretase



Table 1. Patent natural product with structure against CSCs. Patent number

Bioactive

Structure

Targets for inhibiting CSC: markers

WO2013028051 Koetjapic acid

H

O O

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O O

US8183297

Resveratrol (trans-3,5,4¢trihydroxys-tilbene)

CD133+/CD133--

O

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O

O

WO2012171114 EGCG

CD44/CD24

O

O

O

O

O

O

O

O

O

O

O

US2013089627

4-Acetyl-antroquinonol B

O

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H

O

O

O

O O

O

OH

WO2012159085 Embelin

CD133 (lung) and CD44

Epithelial to mesenchymal transition markers

O

O OH

CSCs: Cancer stem cells; EGCG: Epigallocatechin-3 gallate.

complex and the Notch signaling pathway. Curcumin (diferuloylmethane; I,7-bis-(4-hydroxy-3-methoxyphenyl)1,6-heptadiene-3,5-dione) is the major pigment in turmeric powder that possesses anti-inflammatory and antioxidant

properties to inhibit the growth of transformed cells and colon carcinogenesis at the initiation [48]. It has been reported that curcumin synergizes with the combination treatment of 5-fluorouracil (5-FU) and oxaliplatin (hereafter referred to


5

Liver cancer Lupeol (lup-20(29)-en-3b-ol), is a triterpene found in fruits and vegetables, possesses strong antioxidant, anti-inflammatory, antiarthritic, antimutagenic, antimalarial and antitumor activities in in vitro and in vivo systems by inhibiting Ras and Fas signaling pathways [59]. Hepatocellular carcinoma (HCC) development has been reported driven by a small population of cells called tumor-initiating cells (T-ICs) [60]. The liver T-ICs have been identified by several cell surface antigens such as CD133, CD90 and these T-ICs are capable of selfrenewal and are chemoresistant to chemotherapeutic drugs [61,62]. Lupeol was able to modulate the self-renewal ability of liver T-ICs present in both HCC cell lines and clinical samples by decreasing CD133 expression and chemosensitizing HCC cells to chemotherapeutic treatments through the PTEN-Akt-ABCG2 pathway. 8-Bromo7-methoxychrysin (BrMC) is a synthetic derivative of chrysin, a natural and biologically active flavone extracted from many plants, honey and bee propolis [63]. BrMC has been shown to inhibit CSC-like properties of liver CSCs isolating the CD133+ subpopulation from MHCC97 cells resulting in decrease of b-catenin expression [64]. 4.2

Breast cancer Sulforaphane (SF) was found to be converted from glucoraphanin, a major glucosinolate in broccoli/broccoli sprouts [65]. The chemoprevention properties of SF are against cancer [66]. SF was shown to target pancreatic T-ICs [67]. Moreover, SF eliminated breast cancer stem-like cells in vivo, thereby abrogating tumor growth after reimplantation of primary tumor cells into mice, via downregulation of the Wnt/b-catenin self-renewal pathway [68]. These 4.3

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findings support the use of SF for chemoprevention against breast CSCs. Resveratrol (3,4¢,5-trihydroxystilbene) is a phytochemical which is abundantly found in natural foods including grapes, red wine, berries and peanuts [69]. It shows a wide spectrum of pharmacological effects and is considered to reduce the risk of cancer [56]. Resveratrol was capable of suppressing lipid metabolism by blocking the fatty acid synthase expression followed by induction of the pro-apoptotic genes DAPK2 and BNIP3 in isolated cancer stem-like cells (CD24--/CD44+/ESA+) from MDA-MB231 cells and in an animal xenograft model [70,71]. Genistein (4,5,7-trihydroxyisoflavone), a natural isoflavone phytoestrogen found in soybeans, has multiple functions on antitumor effects [72]. Genistein inhibits CD44+CD24-- cell population in MCF-7 cells by downregulating Hedgehog-Gli1 signaling pathway in vivo and in vitro [73]. In addition, it also effectively attenuate mammosphere formation in vitro, reflecting their potential inhibitory effects on CD44+/CD24-/ESA+ subpopulation isolated from MDA-MB-231 cells affecting self-renewal and expansion in vivo. The mechanism is due to inhibition of PI3K/Akt signaling, associated with upregulation of PTEN expression [74]. Ginseng is the most widely recognized medicinal herb. The beneficial effects of ginseng can be attributed to its chemical components, mainly dammarene-type triterpene saponins, which are commonly known as ginsenosides [75] and has inhibitory effects on the migration of tumor cells and significant antiproliferative effects on various cancer cell lines [76]. The pharmacological activities of ginsenoside metabolites are superior to those of the parent ginsenosides, for example, ginsenoside Rb1 was converted to ginsenoside F2 (F2) in human intestinal bacterial enzymes after oral ingestion [77]. F2 suppresses the proliferation of breast cancer cells resistant to anticancer drugs (breast CSC) by modulating apoptotic and autophagic fluxes via the phosphorylation of p53 [76]. Piperine, isolated from black and long peppers, has been reported to reduce cancer incidence in chemical rodent models [78]. It is able to inhibit breast stem cell self-renewal through inhibition of Wnt signaling [79]. Polyphenols make up ~ 40% of the dry weight of green tea leaves, and include epigallocatechin-3 gallate (EGCG), a compound with significant anticancer qualities [80]. EGCG decreased growth of pre-existing tumors derived from ALDH+ stem-like breast cancer cells (SUM-149) and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density [81,82]. Oxymatrine, a potent monosomic alkaloid extracted from Chinese herb Sophora japonica (Sophora flavescens Ait.) possesses anti-inflammatory activities [83]. Oxymatrine treatment of MCF-7 cells not only caused a dramatic decrease in the SP population, but also the downregulation of the activity of Wnt/b-catenin signaling pathway [84]. The Antrodia camphorate extract contained 4-acetyl-antroquinonol B which was assayed against breast CSCs [85]. Embelin was found to inhibit breast and prostate CSCs via multiple mechanisms. This non-toxic bioactive could be

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as 5-FU + Ox) to inhibit the growth of colon cancer cells [49]. Curcumin together with 5-FU + Ox [48] or dasatinib (a Src inhibitor) [50] have been more potent than curcumin in reducing CD44 and CD166 in chemo-resistant colon cancer cells. In addition, a novel curcumin analogue, GO-Y030 [51], has been shown to inhibit tumor growth of ALDH+/CD133+ cells in the mouse model via reduction of signal transducer and activator of transcription 3 (STAT3) phosphorylation [52]. The transmembrane protein CD133 (prominin-1 or AC133) and ALDH were reported as colon CSC marker [53,54]. Furthermore, curcumin-loaded micelles had reduced subpopulations of CD44+/CD24+ cells (putative colorectal CSC markers) [55]. Take together, curcumin could be an effective treatment strategy for preventing the emergence of colon CSCs. Ursolic acid (UA), a pentacyclic triterpenoid, has been identified in apples, pears and prunes, and appears to be protective against cancer [56]. UA has been shown to induce caspase-3 cleavage of ALDH+/CD133+ colon cancerinitiating cells through inhibiting STAT3 phosphorylation [57]. Koetjapic acid was effective against CSC of colon by downregulation of Wnt pathway and suppression of Myc expression [58].

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Oral cancer Honokiol had been shown to exert various biological effects, including muscle relaxation, anti-inflammation, antioxidant activity, various protecting effects against hepatotoxicity, neurotoxicity, thrombosis, and angiopathy and anticancer effects on various types of cancer cells [87]. Furthermore, honokiol has been shown that reduced the proportion of SP inhibited the CD44 and Wnt/b-catenin and is potential application in CSC targeted therapy of oral cancer [87]. 4.5

Prostate cancer

5.

Expert opinion

Significant advances have been made recently in the discovery, development and validation of novel natural products that target CSCs, thereby preventing tumor recurrence and metastasis, and, hopefully, contributing to the cure of cancer. Many novel tumor-targeted drugs, including tyrosine kinase inhibitors and monoclonal antibodies raised against tumor-specific cell surface proteins, also fail to eliminate CSCs [101], so that there is an urgent need for novel compounds that effectively target CSCs for the use in elaborated clinical settings, preferably in combination with conventional cytostatic drugs and novel tumor-targeted agents. In this context, the promising candidate drug is natural products, which has recently been documented to effectively eliminate CSCs in different types of human cancers in vitro and in xenograft mice. Natural products are advantageous in two aspects as chemoprevention agents: i) they usually have very low or no toxicity, in contrast to most chemotherapy drugs; and ii) many of these compounds have shown potential as an adjunct to chemotherapy drugs in some clinical trials. Furthermore, the future clinical use of these natural products may represent a powerful strategy for eradicating CSCs in cancer patients. In Phase I and II clinical trials, curcumin in combination with gemcitabine [102] and docetaxel [103] has been proven successful in the treatment of advanced pancreatic and breast cancer, respectively. Natural products may gain considerable importance in stem cell biology for both tissue regeneration and for protection of normal tissue against the side effects of cancer chemoand radiotherapy. This population of CSCs can give rise to tumor relapse even after chemotherapy has achieved complete clinical remission of tumors. The results obtained with natural products in the past few years are promising, as several natural products have been reported to attack CSCs. Furthermore, many of these natural products also improve the efficacy of chemo- and radiotherapy, making them ideal partners for combination therapy regimens. More work is required to study in detail the molecular mechanisms, the clinical efficacy and the long-term safety of natural products that target CSCs, with the aim of providing novel and highly effective therapies for patients in cancer.

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Gossypol, a yellowish compound produced by cotton plants (Gossypium species), has a long history of use in Chinese folk medicine and has been extensively studied for its use as a male contraceptive agent [88]. Many studies have shown that gossypol inhibits cell proliferation and prevents metastases of many types of cancers [89,90]. Gossypol has been reported to reduce the viability of tumor initiating CD44+ prostate cancer cell lines in vitro and associate with increased DNA damage, activation of p53 and induction of apoptosis [89]. Genistein (4,5,7-trihydroxyisoflavone), a major isoflavone constituent of soybeans and soy products, has been shown to exhibit potent antiproliferative effect on various cancers [91]. A recent study has demonstrated that genistein has anti-CSC effects, as evidenced by the suppression of self-renewal capacity in vitro and tumor formation in vivo. These effects were due to the inhibition of Hedgehog-Gli signaling and CSC markers CD44 expression [92]. SF is a naturally occurring anticancer, antidiabetic and antimicrobial compound mainly found in cruciferous vegetables [93]. SF has been reported to strongly increase the anticancer efficacy against prostate CSCs. Meanwhile, combination of SF with a cytotoxic drug efficiently induced apoptosis along with inhibition of self-renewing potential, ALDH1 activity, clonogenicity, xenograft growth and relapse of GEM-treated tumor cells in nude mice [94]. Paclitaxel (PTX) with cyclopamine, a natural steroidal alkaloid which inhibits the Hedgehog pathway resulting in decreased proliferation and increased apoptosis [95], has recently shown to reverse PTX chemoresistance and eliminate SP fraction in androgen-independent, metastatic prostate cancer cell lines. In addition, a recent study has displayed that N-(2-hydroxypropyl) methacrylamide copolymer--cyclopamine conjugate decreased stem cell marker CD133 expression in prostate cancer epithelial cell model, RC-92a/hTERT cells, with stem cell properties [96].

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low bioavailability and low stability, which lead to a reduction in its cancer-preventive activity. Therefore, peracetylated EGCG (AcEGCG) was synthesized to increase the lipophilicity and membrane permeability and improve the bioefficacy of EGCG [98]. Furthermore, AcEGCG markedly inhibited activation of PKD1, which plays an important role in keratinocyte functions that regulate proliferative and antidifferentiative processes [99] in CD34+ skin stem cells [100].

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administered at a dose ranging from 0.1 to 300 mg/kg body weight/day [86].

Skin cancer EGCG is the most abundant and powerful antioxidant in green tea for cancer chemoprevention [97]. However, EGCG is hydrophilic and exhibits poor cellular absorption, 4.6


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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest 12.

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Chien-Hsing Lee1 & Chung-Yi Chen†2 PhD † Author for correspondence 1 Min-Hwei Junior College of Health Care Management, Department of Nursing, Tainan City, Taiwan 2 Fooyin University, School of Medical and Health Sciences, Department of Medical Laboratory Science and Biotechnology, 151, Ching-Hsueh Road, Ta-Liao District, Kaohsiung 831, Taiwan Tel: +886 7 7811151; ext.6200; Fax: +886 7 7834548; E-mail: [email protected]

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Burnett J, Newman B, Sun D. Targeting cancer stem cells with natural products. Curr Drug Targets 2012;13(8):1054-64 Many novel tumor-targeted drugs, including tyrosine kinase inhibitors and monoclonal antibodies raised against tumor-specific cell surface proteins, also fail to eliminate CSCs.

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chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol 2011;68(1):157-64


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