The use of natural products in colorectal cancer drug discovery.

Review

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by University Library Utrecht on 03/15/15 For personal use only.

The use of natural products in colorectal cancer drug discovery 1.

Introduction

2.

Properties of NPs

3.

Classification of NPs

4.

NPs as anti-cancer agents

5.

NPs for clinical use in the treatment of CRC

6.

NPs evaluated in clinical trials

7.

Other NPs for anti-cancer drug discovery

8.

Conclusion

9.

Expert opinion

Koh Miura†, Masayuki Satoh, Makoto Kinouchi, Kuniharu Yamamoto, Yasuhiro Hasegawa, Yoichiro Kakugawa, Masaaki Kawai, Kiyoshi Uchimi, Hiroki Aizawa, Shinobu Ohnuma, Taiki Kajiwara, Hiroto Sakurai & Tsuneaki Fujiya †

Miyagi Cancer Center, Department of Surgery, Natori, Japan

Introduction: Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a strategy of developing targeted agents by screening libraries of synthetic compounds. However, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and was applied in standard regimens for metastatic colorectal cancer (CRC) worldwide. Additionally, polysaccharide K is approved for CRC in Japan and Taiwan in combination with cytotoxic agents. However, after the approval of irinotecan in 1996, no anti-cancer agents derived from NPs have been approved for CRC. Areas covered: This review discusses NPs that are currently under investigation for the treatment of CRC. In addition, other NPs derived as purified ingredients and crude extracts are listed and also discussed. Expert opinion: The use of NPs for the discovery of anti-cancer agents has not been fully investigated. New technologies that are currently applied for synthetic compounds may be utilized for anti-cancer drug discovery including NPs for CRC. Keywords: anti-cancer agent, cancer prevention, colorectal cancer, drug discovery, natural products Expert Opin. Drug Discov. [Early Online]

1.

Introduction

According to the GLOBOCAN 2012 trial conducted by the International Agency for Research on Cancer in 2014 [1], colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide, and, in more developed regions of the world, approximately 758,000 new cases and 333,000 deaths due to CRC were estimated to have occurred in 2012, accounting for 12.1% of all new cancer cases. The latest data from the American Cancer Society of CRC on the incidence, survival and mortality of cancers in the US were reported in 2014 [2-4]. As indicated in the National Comprehensive Cancer Network guidelines [5], surgical treatment is usually chosen for resectable CRC patients, whereas chemotherapeutic regimens, including 5-fluorouracil (5-FU)-based agents and leucovorin (LV) with oxaliplatin or irinotecan, and the addition of biologically targeted agents, such as anti-EGFR antibodies or anti-VEGF antibodies, are considered in cases of metastatic CRC (mCRC). Recently, ziv-aflibercept, a recombinant protein with VEGF receptors 1 and 2, and regorafenib, an oral multi-tyrosine kinase inhibitor, were added to standard therapies for mCRC in the US and other countries. In addition, novel therapeutic agents for CRC are currently under development [6]. Nivolumab, an anti-programmed death-1 antibody, has shown promising results in patients with refractory CRC [7,8]. Furthermore, treatments 10.1517/17460441.2015.1018174 © 2015 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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K. Miura et al.

Article highlights. .

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Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a target-driven strategy with synthetic compounds; however, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and has been widely used in standard regimens for metastatic colorectal cancer (CRC). However, since the approval of irinotecan in 1996, no anti-cancer agents derived from NPs have been approved for the treatment of CRC. Currently, a variety of NPs, including curcumin, talaporfin sodium, eicosapentaenoic acid, resveratrol and bioflavonoids, are being evaluated in clinical trials of CRC with respect to their efficacy for cancer prevention and application in biomarker analyses. Other NPs derived as purified ingredients and crude extracts are also currently under investigation for drug discovery. In order to promote the discovery of anti-cancer agents with NPs, new technologies being applied to synthetic compounds should be further utilized for research on NPs.

This box summarizes key points contained in the article.

with BBI608, a cancer stem cell inhibitor for CRC, as well as therapies directed at BRAF-mutant CRC and a reovirus targeting KRAS-mutant CRC are also under development [6], and the beneficial effects of celecoxib as an prostaglandinendoperoxide synthase 2 inhibitor and other related structures (coxibs) in reducing the risk of CRC have been demonstrated in both in vivo and in vitro studies with CRC cells [9]. Natural products (NPs) are substances produced by living organisms and, in medicinal chemistry, are more significantly restricted to secondary metabolites that are not essential for survival but produce evolutionary advantages and therapeutic benefits. In the long history of human medicine, a myriad of NPs are expected to have been used to treat diseases [10]. Historically, crude extracts of NPs were the major sources of medications. In the nineteenth century, it became possible to purify active ingredients from crude extracts, and, since the 1950s, several NPs have been identified to be anti-cancer agents. However, as pointed out by Koehn [10], since the beginning of the 1980s, the pharmaceutical industry has gradually turned away from efficacy-driven drug discovery with NPs and instead adopted a process-based target-driven strategy, relying on high-throughput biochemical screening of large collections of synthetic compounds. After the 2000s, novel anti-cancer targeted agents for CRC in the formulations of monoclonal antibodies and small synthetic compounds have been developed, as indicated earlier; however, no agents for CRC derived from NPs were developed during this 2

period. A series of new technologies were also applied according to process-based target-driven strategies in this time period, and these technologies can also surely be utilized for anti-cancer drug discovery with NPs. NPs exhibit more complex structures and diverse features than synthetic compounds artificially synthesized by humans, and new technologies may be further utilized to assess NPs. For the aforementioned reasons, NPs have received renewed focus as a rich repository for drug discovery. On the other hand, patients with mCRC cannot be cured with current chemotherapy regimens alone, and the development of new types of anti-cancer agents is required. In this review, we summarize current information regarding NPs presently being evaluated for clinical use in clinical trials and in stages of preclinical development for CRC and discuss how novel technologies may be utilized for drug discovery with NPs for CRC. 2.

Properties of NPs

In 1999, comparing several drug databases, Henkel et al. clarified the differences in chemical structures between NPs and synthetic compounds [11]. Their findings revealed that the NPs applied in the clinical setting have higher molecular weights than synthetic compounds and contain a lower number of nitrogen, halogen and sulfur atoms, with an increased content of oxygen. In addition, NPs contain a larger fraction of compounds with sp3-hybridized bridgehead atoms, and the average number of rings and chiral centers per molecule is greater. As a result, NPs can be described as being sterically more complex structures [11]. Furthermore, in regards to the distribution of chemical structures, a large fraction of terpenes (~ 35%) and alkaloids (20%), in addition to peptides (17%) and alicycles (19%), are found in NP databases. In 2009, Lovering et al. proposed that two simple measurements of molecular complexity are important for successful drug discovery: carbon bond saturation, defined as the number of sp3-hybridized carbons/total carbon count, and the presence of chiral centers [12]. 3.

Classification of NPs

NPs exhibit diversity in their biological functions and chemical structures as well as biosynthetic pathways. Hence, they can be classified based on these categories. From the aspect of chemical structures, a classification of NPs derived from plants was previously proposed [13]; however, such a classification has not been reported for other organisms. Tables 1 and 2 show the classification for NPs originating from plants, which was proposed by Bravo et al. [13], and, in the current review, we apply this classification as the standard for all NPs, not only those derived from plants but also those from other organisms. Polyphenols are the most numerous and widely distributed group of substances in plants and can be divided into at least 16 different classes depending on their chemical structure [13]. Table 1 illustrates the main classes of polyphenolic compounds.

Expert Opin. Drug Discov. (2015) 10(4)

The use of natural products in colorectal cancer drug discovery


Table 1. Main classes of polyphenolic compounds. Class

Basic skeleton

Simple phenols

C6

Benzoquinones

C6

Phenolic acids

C6-C1

Acetophenones

C6-C2

Phenylacetic acids

C6-C2

Hydroxycinnamic acids

C6-C3

Phenylpropenes

C6-C3

Coumarins, isocoumarins

C6-C3

Basic structure OH

O

O

COOH

COCH3

CH2-COOH

CH=CH-COOH

CH2-CH=CH2 O

O O O

Chromones

C6-C3

O

Naphthoquinones

C6-C4

O O

Xanthones

C6-C1-C6

O O

Stilbenes

C6-C2-C6

O

Adapted from reference [13] with permission from John Wiley and Sons.


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K. Miura et al.

Table 1. Main classes of polyphenolic compounds (continued). Class

Basic skeleton

Anthraquinones

C6-C2-C6

Flavonoids

C6-C3-C6

Basic structure O

O 3′


2′ 8

O 1 C

1

7 A 6

2

5′

1′ 6′ 3

2 5

Lignans, neolignans Lignins

4′ B

4

(C6-C3)2 (C6-C3)n

Adapted from reference [13] with permission from John Wiley and Sons.

Table 2. Classification of flavonoids. Class

Basic structure

Class

Basic structure

Leucoanthocyanidins

Chalcones

O O OH OH

Dihydrochalcones

Anthocyanidins O

+

O

Aurones

O

Isoflavonoids

O

O

O

O

CH

O

Flavones

Biflavonoids O

O

O O Adapted from reference [13] with permission from John Wiley and Sons.

4


O

O


Table 2. Classification of flavonoids (continued). Class

Basic structure

Class

Flavonols

Basic structure

Proanthocyanidins or condensed tannins O

O

CH3

OH

O O


CH3

O

CH3 CH3

Dihydroflavonols O

OH O

Flavanones O

O

Flavanols O

OH Adapted from reference [13] with permission from John Wiley and Sons.

Currently, > 8000 NPs with a phenolic structure have been identified [14]. Among polyphenols, flavonoids can be further classified into at least 13 subgroups (Table 2). 4.

NPs as anti-cancer agents

Ganesan analyzed the structural properties of NPs approved as anti-cancer agents between the 1940s and 2010 and demonstrated that the partition-coefficient (Log P) of lipophilicity and number of hydrogen bond (H-bond) donors (OH and NH) are the two most important parameters of bioavailability. In addition, most NPs applied as anti-cancer agents maintain a computationally calculated partition-coefficient (Clog P) of £ 4 and number of H-bond donors of £ 5 [10]. From the 1940s to 2010, excluding those contained in formulations with steroids or peptide hormones, at least 42 NPs were approved as anti-cancer agents [10,15]. Among these compounds, plants have been a great source of secondary

metabolites, with significant chemical diversity. As summarized by Bailly in his review [16], after irinotecan and docetaxel were approved in 1996, in the period from 1997 to 2006, no novel categories of NPs were approved by the FDA for use as anti-cancer agents. The main reason for this finding is that, during this time, the pharmaceutical industry shifted to a target-driven strategy employing synthetic compounds. However, in 2007, three new anti-cancer agents derived from NPs were approved: the microtubule-targeted epothilone derivative ixabepilone (BMS-247550), the DNA-alkylating marine alkaloid trabectedin (Ecteinascidin-743) and the inhibitor of mammalian target of rapamycin (mTOR) protein kinase temsirolimus (CCI-779) [16]. In addition, new formulations of known NP-derived agents, such as nanoparticle formulations and oral formulations, have recently been developed. However, since the approval of irinotecan in 1996, no anticancer agents derived from NPs have been approved for CRC.


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K. Miura et al.

A.

Camptothecin

B.

O

Topotecan O

O

O

O

OH N

H3C

N

N

O

O

OH N

H3C

Irinotecan

O

O

OH N

C.

H3C

N


H3 C H3C

N O

CH3 HO

O N

N

D.

SN-38

E. O

Diflomotecan

F. Gimatecan O

O

O

O

O O

O

OH O

N

OH

H3C

OH N

N

H3 C

H

H3C N

N

H3C

N

H 3C H3 C

O

N

CH3

HO F

F

Figure 1. Chemical structure of camptothecin and its derivatives. (A) Camptothecin; (B) topotecan; (C) irinotecan; (D) SN-38; (E) diflomotecan; and (F) gimatecan.

5.

NPs for clinical use in the treatment of CRC

In 1966, camptothecin (Figure 1A) was isolated from Camptotheca acuminata Decne and discovered during extensive screening of random plant products [17]. In 1988, it became clear that camptothecin acts via a completely new mode of action as an inhibitor of topoisomerase I [18]. However, clinical studies of camptothecin subsequently demonstrated its unfavorable properties, including insufficient water solubility, substantial toxicity, rapid inactivation via lactone hydrolysis 6

and so on [19]. In order to overcome these insufficiencies, camptothecin derivatives were further studied, and two derivatives are currently applied clinically: topotecan (Figure 1B) and irinotecan (Figure 1C). Compared to camptothecin, topotecan contains an additional C9 tertiary amine side chain and C10 hydroxyl group, both of which enhance aqueous solubility. Topotecan is used for the treatment of advanced ovarian cancer, treatment-sensitive small cell lung cancer and childhood malignant tumors but not CRC. In contrast, irinotecan is a prodrug formulation of the decarboxylated



Plc vs resveratrol, 14 days Andrographolide vs andrographolide + Cape, up to 100 months EPO906 + celebrex (one arm), i.v. every 3 weeks CapeOX vs TLBZT + CapeOX, 14 days on and 7 days off for TLBZT until PD Plc + IRI vs KD018 + IRI, 4 days every 2 weeks for KD018/Plc

01070355

02069561

00920803 01993472

EPA [33-35]

Resveratrol [36] Andrographolide

01975454

00730158

Herbal therapy (TLBZT) [38]

Herbal therapy (KD018) [39]

mCRC

mCRC

mCRC

mCRC with LM, followed by surgery UC at CRC risk, awaiting polypectomy mCRC with LM Elderly patients with mCRC

mCRC with LM

mCRC with LM

mCRC with LM

mCRC

Healthy volunteers Rectal cancer, followed by surgery mCRC

Condition

88

I -- II

Safety and efficacy

Safety and efficacy PFS and OS

165

72

I -- II II

80

I -- II

9 308

25

483

25

25

III

II

II

20

51

I -- II I

15 -- 36 45

I II

Recruiting

Active, not recruiting Recruiting

Completed Not yet recruiting

Recruiting

Completed

Completed

Completed

Completed

Recruiting

Recruiting

Completed Active, not recruiting

Phase Enrollment Status

Gut microbiota II and metabolomic profiles Safety and PK I Safety and II efficacy

Safety and efficacy

Safety and efficacy Safety and efficacy OS and PFS

Safety and efficacy Safety and PK

MTD pCR

Outcome

Dec 2008, *Jun 2018

Apr 2012, *Apr 2015

Oct 2004, *Jan 2016

Aug 2008, Nov 2009 Nov 2013, *Jun 2016

Jan 2014, Nov 2014

Apr 2010, Oct 2011

Feb 2007, Oct 2011

May 2004, Apr 2007

Oct 2003, Sep 2006

Jun 2013, *Jun 2020

Feb 2012, *Feb 2019

Dec 2001, Sep 2007 Jul 2008, *Jul 2015

Start date, end date*

US

CN

US

UK CN

IT

UK

US

US

US, DE

US

UK

US US

Country

*Anticipated time as of September 2014. Cape: Capecitabine; CapeOX: Capecitabine + oxaliplatin; CN: China; CRC: Colorectal cancer; CT: Chemotherapy; DE: Germany; EPA: Eicosapentaenoic acid; IRI: Irinotecan; IT: Italy; Litx: Light infusion technology; LM: Liver metastasis; Mcrc: Metastatic colorectal cancer; MTD: Maximum tolerated dose; OS: Overall survival; pCR: Pathologic complete response; PD: Progression disease; PFS: Progression-free survival; Plc: Placebo; PSK: Polysaccharide-K; RT: Radiotherapy; TLBZT: Teng-long-bu-zhong-tang; UC: Ulcerative colitis.

00159484

Epothilone

[37]

No intervention vs EPA, 90 days

00068068

Talaporfin sodium [30,31] Talaporfin sodium [30,31] Talaporfin sodium EPA [32] FOLFOX4 (FOLFIRI) vs Litx + FOLFOX4 (FOLFIRI) Plc vs EPA, 2 -- 6 weeks

01859858

Curcumin

00440310

01490996

Curcumin [29]

Litx (one time) followed by CT

Curcumin capsule Plc + Cape/RT(45Gy) vs curcumin + Cape/RT (45Gy), 28 days FOLFOX vs curcumin + FOLFOX, 6 months Curcumin + IRI (one arm), 19 -- 28 days Litx (one time) followed by CT

00027495 00745134

Curcumin [25] Curcumin [26-28]

00083785

Intervention

Natural product NCT ID [Ref.]

Table 3. Clinical trials for anti-cancer efficacy [25-39].



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K. Miura et al.

active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin) (Figure 1D) and is currently clinically used in standard regimens for mCRC, such as FOLFIRI. A large number of clinical studies of irinotecan have been reported, which are not the focus of this review. Notably, irinotecan analogues contained in oral administration formulations, such as diflomotecan (BN80915) (Figure 1E) [20] and gimatecan (ST1481) (Figure 1F) [21], are under investigation in preclinical studies. PSK (KRESTIN) is protein-bound polysaccharide K isolated from the cultured mycelium of the Basidiomycete Coriolus versicolor, with an average molecular weight of 100,000 and 18 -- 38% protein [22]. The efficacy of PSK against cancer is mediated via several pathways, including recovery from immunosuppression induced by TGF-b and anti-tumor immune responses, such as promoting the maturation of dendritic cells and enhancing the efficacy of chemotherapy via the induction of apoptosis, inhibition of metastasis and others [22]. In 2010, Lu et al. reported the efficacy of PSK as a novel toll-like receptor 2 (TLR2) agonist that mediates the inhibition of tumor growth via the stimulation of CD8+ T and NK cells [23]. Currently, PSK is approved for use in Japan and Taiwan for the treatment of CRC in addition to gastric cancer and small cell lung cancer in combination with cytotoxic agents. Primarily in Japan, through the 1990s -- 2000s, the efficacy of PSK in the postoperative adjuvant setting for CRC was evaluated in randomized studies, including PSK versus placebo, mitomycin C and tegafur (5-FU prodrug) suppositories plus PSK versus mitomycin C plus tegafur suppositories and others. As reviewed by Maehara et al. [22], in all of the five randomized studies conducted at that time, the experimental arms treated with PSK showed better results than the control arms treated without PSK. Currently, several studies of PSK in combination with various chemotherapy regimens in the setting of CRC are ongoing, including oral tegafur with uracil (UFT) plus LV versus UFT, LV plus PSK, UFT plus LV versus UFT plus PSK and curative surgery alone versus curative surgery followed by UFT plus PSK. 6.

NPs evaluated in clinical trials

In this review, clinical trials of NPs surveyed on the FDA website [24] are listed in Tables 3 and 4. These data are current as of September 2014. Trials with an unknown status were excluded, as were those assessing steroids, peptide hormones, vitamin D, vitamin E and folic acid. Clinical trials of anti-cancer efficacy Trials of NPs to determine their anti-cancer efficacy and 15 related references [25-39] are summarized in Table 3. Curcumin is a naturally occurring polyphenolic phytochemical derived from Curcuma longa Linn. The chemopreventive mechanisms of curcumin have been investigated extensively, and curcumin has been demonstrated to decrease proliferation and induce cell-cycle arrest and apoptosis [29]. 6.1

8

The NCT00027495 study (Table 3) is a Phase I study conducted to determine the maximum tolerated dose of curcumin in healthy volunteers, the results of which were reported in 2008 [25]. In the NCT00745134 study [26-28], the effects of curcumin on the efficacy of preoperative chemoradiotherapy were investigated. This study is based on the findings of previous studies of the effects of curcumin on radiosensitivity using colon cancer cells in vitro [26] and the anti-cancer efficacy of capecitabine (5-FU prodrug) in vivo [27]. Both the NCT01490996 [29] and NCT01859858 studies investigated the effects of curcumin on the treatment efficacy of chemotherapy. Light infusion technology (Litx) was recently developed as a targeted treatment for many different solid tumors and consists of the light-activated drug talaporfin sodium (LS11) activated intratumorally by light-emitting diodes. In a study by Kujundzic´ et al. [31], light-emitting diodes were inserted percutaneously into the target tumor, and LS11 was administered intravenously followed by light infusion starting 15 -- 60 min later for 2.8 h. In that study, the Litx system was found to be safe when treating CRC patients with liver metastases, and there were no cumulative toxicities when combined with standard systemic chemotherapy regimens [31]. Based on these results, a Phase III study employing the Litx system was conducted among 483 CRC patients with liver metastases treated with systemic chemotherapy (FOLFOX4 or FOLFIRI; NCT00440310, Table 3). Eicosapentaenoic acid (EPA) is a naturally occurring omega-3 polyunsaturated fatty acid found in oily fish. In experimental models, EPA is thought to have an anti-CRC activity. The NCT01070355 study tested whether EPA reduces markers of tumor growth and is safe in CRC patients with liver metastases awaiting surgery. The results of the NCT01070355 study in the UK were reported in 2014 [32] and subsequently indicated that EPA may have antiangiogenic properties and that preoperative treatment with EPA may improve overall survival. Based on these results, a Phase III clinical study was warranted [32]. Another study of EPA was conducted in Italy in 2014 (NCT02069561), relying on the findings of previous studies both in vitro [33,34] and in vivo [35]. For example, D’Angelo et al. found that this combination completely inhibited mTOR signaling, leading to changes in protein translation, reduced cell proliferation and induced apoptosis in CRC cells [33]. Resveratrol (SRT501) is a phytoalexin with a stilbene structure (Table 1) produced by certain plants when damaged by pathogens, such as bacteria or fungi. It is believed to have apoptotic and antiproliferative effects via the induction of Fas redistribution and inhibition of Wnt signaling [36]. The purpose of the NCT00920803 study was to determine the safety and tolerability of resveratrol in CRC patients with liver metastases [36], and the results supported further clinical explorations of resveratrol. Although the efficacy of resveratrol has been cumulatively reported, in 2010, GlaxoSmithKline



00927485, 00641147

00433576 00256334 01948661

Curcumin

Resveratrol [45-47] Resveratrol [48,49] Anthocyanin extract and curcumin Flaxseed lignans

01916239

01344538

PGE2 in ACF

50 60

I -- II

65 II

II

150

60

I -- II II

80

20 11 100

50

40

48

II

I I II

II

I

II

14

58

II -- III I

120

2941

382

50 130

II

III

II

II II

Start date, end date*

Active, not recruiting

Completed

Completed

Recruiting

Completed

Recruiting

Completed Completed Recruiting

Recruiting

Completed

Completed

Completed

Completed

Recruiting

Recruiting

Suspended

US US

Country

Jun 2012, *Sep 2015

Apr 2007, Dec 2012

Aug 2005, May 2008

Sep 2012, *Jul 2015

Oct 2009, Apr 2011

Oct 2012, *Aug 2016

Dec 2006, Mar 2009 Jul 2005, Apr 2009 Mar 2014, *Sep 2015

Oct 2010, *Jun 2015

Nov 2010, Jan 2013

Oct 2006, Sep 2008

Dec 2005, Dec 2008

Nov 2006, Apr 2008

Jun 2012, *Jan 2018

ES

US

US

US

IT

US

US US IT

US

US

US

US

UK

US

*May 2015, *Dec DE 2016 Nov 2011, *Mar 2018 DE

Recruiting Oct 2010, *Jun 2015 Terminated Aug 1996, Jul 2006

Phase Enrollment Status

*Anticipated time as of September 2014. ACF: Aberrant crypt foci; APs: Adenomatous polyps; CRC: Colorectal cancer; DE: Germany; EPA: Eicosapentaenoic acid; ERa: Estrogen receptor a; ERb: Estrogen receptor b; ES: Spain; FAP: Familial adenomatous polyposis; IHC: Immunohistochemistry; IT: Italy; MTD: Maximum tolerated dose; PGE2: Prostaglandin E2; Plc: Placebo; PUFA: Polyunsaturated fatty acids.

Ginger root extract [51-54] Pomegranate extract [55]

01661764

Marine-derived n-3 PUFA [50] Legume diet

00339469

01402648

ERb agonists and lignin

01619020

Curcumin (one arm), 30 days

01333917

Curcumin

Smokers with ACF, awaiting biopsy CRC, awaiting rectal biopsy FAP, awaiting biopsy

FAP

Gene expressions and IHC Plc vs curcumin, up to 5 years DNA methylation, Ki67, apoptosis and others Resveratrol (one arm), 8 days CRC, awaiting surgery COX2 and Ki67 Resveratrol (four doses), 14 days CRC, awaiting surgery Wnt signaling Plc vs Mirtoselect + Meriva, With APs > 1 cm, b-catenin in 28 days awaiting biopsy normal and adenomas Plc vs lignan capsule, 3 days Healthy volunteers, Cell-signaling awaiting biopsy pathways Plc vs Eviendep, 60 days With prior ERa, ERb, TUNEL, polypectomy and CRC Ki67 and others risk, awaiting biopsy Plc vs fish oil supplements, With APs, awaiting Epithelial cell 24 weeks biopsy growth markers High legume diet (four groups), At risk for adenoma Markers in blood, 8 -- 12 weeks recurrence urine and stools Plc vs ginger root extract, Healthy volunteers, PGE2 in mucosa 28 days awaiting biopsy Standard- and new-type CRC, awaiting surgery Gene expressions pomegranate extracts, 15 days and others

Curcumin (one arm), 30 days

Plc vs EPA capsule, 6 months

00510692

EPA [41,42] Plc vs black raspberries, 36 weeks

Plc vs polyphenon E, 6 months

01606124

00770991 Black raspberries [43] Biomarker analysis 00365209 Curcumin [44]

Plc vs green tea extract, 3 years

Neoplasia recurrence Adenoma development Number of rectal ACF Number and size of polyps Number of rectal polyps

After stage II -- III CRC surgery With prior polypectomy With current/prior advanced APs FAP

Flavo-Natin (one arm), 3 years

01360320

Number of polyps Neoplasia development

Outcome

FAP Volunteers with CRC risk

Condition

Plc vs curcumin, 12 months Plc vs sulindac + curcumin + rutin + quercetin, 6 -- 10 weeks

Intervention

Green tea extract [40] Polyphenon E

Cancer prevention Curcumin 00641147 Sulindac, curcu00003365 min, rutin and quercetin Bioflavonoid 00609310

Natural product NCT ID [Ref.]

Table 4. Clinical trials for cancer prevention and biomarker analysis [40-55].



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K. Miura et al.

(Brentford, UK) halted all further development of resveratrol due to its weak efficacy and associated risk of renal failure. Andrographolide is a diterpenoid and the main bioactive component of the medicinal plant Andrographis paniculata. The purpose of the NCT01993472 study was to determine the efficacy and safety of andrographolides combined with capecitabine in the treatment of elderly patients with locally advanced CRC or mCRC [37]. Teng-Long-Bu-Zhong-Tang is a modern anti-cancer herbal formula used in China [38], whose anti-cancer potential against CRC was recently confirmed in vitro. Teng-Long-Bu-Zhong-Tang significantly enhances the anti-cancer effects of 5-FU in CT26 colon cancer cells (NCT01975454) [38]. KD018 (PHY906) is a four-herb Chinese medicine formula first described 1800 years ago [39] and is thought to decrease gastrointestinal toxicity induced by irinotecan and increase the anti-tumor activity of irinotecan in mice models. Lam et al. examined the effects of KD018 [39], and a Phase II study is currently ongoing (NCT00730158). Clinical trials for cancer prevention and biomarker analyses

6.2

Clinical trials of the efficacy of NPs for cancer prevention and biomarker analyses and 16 related references [40-55] are summarized in Table 4. Curcumin, flavonoid (Table 1), green tea extract, polyphenon E and other components have been studied with respect to cancer prevention (Table 4). For example, the purpose of the NCT01360320 study is to investigate the effects of green tea extract epigallocatechin gallate (EGCG) as the major polyphenol of green tea on the incidence of recurrence of colon adenoma [40]. A total of 2028 patients are expected to complete the entire study course up to 2018. Polyphenon E, a tea catechin extracted from natural tea leaves, may prevent or slow the onset of CRC. The purpose of the Phase II trial (NCT01606124) is to study how polyphenon E works in patients with a high risk of CRC. Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form on the inside walls of the colorectum. In 2010, West et al. reported the efficacy of EPA in reducing the number and size of rectal polyps in a population with FAP (NCT00510692) [41], in which the global polyp burden worsened over 6 months in the placebo group, unlike that observed in the EPA group (mean treatment group difference: 0.42 [95% CI: 0.10 -- 0.75], p = 0.011). In 2013, the authors further announced a randomized trial of EPA and/ or aspirin for the prevention of colorectal adenoma (seAFOod Polyp Prevention Trial) [42], for which 904 patients have been recruited. In 2014, Wang et al. reported the outcome of a Phase Ib study of black raspberries in a population with FAP (NCT00770991) [43]. In that study, 7 patients received black raspberry powder orally plus two black raspberry suppositories inserted into the rectum at bedtime, and 7 patients received an oral placebo plus the suppositories. The burden (p = 0.036), but not number (p = 0.069), of rectal polyps significantly decreased following treatment with the black 10

raspberry suppositories in the FAP group. The authors’ next study is currently in the planning stage. As of September 2014, using the two keywords sulindac and curcumin, approximately 30 articles can be found on the National Center of Biotechnology Information website. Clinical studies of NPs for use in biomarker analyses are also listed in Table 4. All of these studies are Phase I or II. A study by Carrol et al. (NCT00365209) is a Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia in smokers with aberrant crypt foci [44], which are clusters of abnormal tube-like glands in the lining of the colon and rectum, formed before colorectal polyps, and may lead to cancer. In addition, biomarkers were also analyzed, in which curcumin was found to reduce the mucosal concentrations of prostaglandin E2 (via the inhibition of cyclooxygenases 1 and 2) and 5-hydroxyeicosatetraenoic acid (via the inhibition of 5-lipoxygenase) in rats. Regarding resveratrol, two groups in the UK and US recently reported their results. In 2010, Brown and coworkers reported decreased expression levels of IGF-I and IGFBP-3 following treatment with resveratrol, which may contribute to its cancer chemopreventive activity [45]. The authors also analyzed the clinical pharmacology of resveratrol and its metabolites as well as the effects of these compounds on cell proliferation in epithelial cells (NCT00433576) [46] and demonstrated that the degree of Ki-67 staining was reduced from 88.0 ± 6.64% in the predose biopsy samples to 83.2 ± 10.0% in the postintervention surgical tissues (n = 20; p = 0.05, paired Student’s t-test). On the other hand, Hope and coworkers reported that a low concentration of resveratrol inhibits Wnt signal throughput in colon-derived cells in vitro (NCT00256334) [48], which may be due in part to the regulation of intracellular b-catenin localization. In 2009, their group also reported the results of a Phase I study indicating that resveratrol inhibits the Wnt pathway in colon tissues [49]. Furthermore, a group at the University of Michigan Medical School reported the findings of biomarker analyses using ginger root extract (NCT01344538) [51-54]. In 2013, this group analyzed the expression levels of the Bax, Bcl-2, p21, hTERT and Ki-67 genes [52] and suggested that ginger reduces proliferation in the normal-appearing colorectal epithelium and increases apoptosis and differentiation. In 2013, they also analyzed the effects of ginger root on the cyclooxygenase-1 and 15-hydroxyprostaglandin dehydrogenase expression in the colonic mucosa [53] and found that the participants at increased risk of CRC had significantly reduced colonic COX-1 protein levels (23.8% ± 41) compared to the placebo group (18.9% ± 52; p = 0.03), whereas the protein levels of 15-PGDH in the colon remained unchanged. 7.

Other NPs for anti-cancer drug discovery

Other NP candidates for anti-cancer drug discovery and 28 selected articles are listed in Table 5 [56-83]. These compounds were surveyed in the National Center of



Table 5. Natural products for anti-cancer drug discovery of colorectal cancer [56-83].


Class Polyphenols Benzoquinones Naphthoquinones Xanthones Stilbenes Anthraquinones Flavonoids Chalcones Flavones Flavonols Flavanones Flavanols Proanthocyanidins Lignans Substances other than polyphenols Alkaloids

Substances [Ref.] Tanshinone IIA Naphthoquinone components [56] a-Mangostin [57], gambogic acid Fluorinated N,N-dialkylaminostilbenes [58], resveratrol Chrysophanic acid Retinoid-chalcones Luteolin [59], fisetin [60], WYC02-9 Green tea catechins [61], EGCG [62] Hesperetin Procyanidin, theaflavin monogallate Anthocyanins [63,64], grape seed proanthocyanidins Honokiol [65], magnolol [66], podophyllotoxin, silibinin, hydnocarpin Antofine [67,68], avenanthramide, neo-clerodane diterpenoid alkaloids, taspine

Terpenes

Maslinic acid [69], talaporfin, novel triterpenoids, ent-clerodane diterpenoids, curcuphenol, picrotoxin, solaniol, triptolide, carnosic acid, koetjapic acid, andrographolide, plaunotol, geranylgeraniol

Sapogenin

Yerba mate tea and mate saponins [70], Paris saponin VII [71]

Other substances

Polyacetylenes and polyenes [72], chromane derivatives [73], grifolin [74], g-oryzanol [75], yuanhuacine [76], chartreusin [77], simvastatin and lovastatin [78], TPU942 and its derivatives [79], PTZ0025, phytic acid, b-sitosterol, diallyl sulfide, brefeldin A, parthenolide, norcantharidin, protopanaxadiol, melanoidin, evodiamine, 1’-acetoxychavicol acetate, panaxadiol, renieramycin, pyrazolone derivatives, b-asarone, phthalide, turmerone

Other extracts

Apple extracts [80,81], American ginseng (Panax quinquefolius Linn.), black raspberry extracts [82], rosemary extracts [83], quince extracts, pomegranate extracts, propolis, fucoidan, herbal fixed combination STW 5 (Iberogast), Goshajinkigan

EGCG: Epigallocatechin gallate.

Biotechnology Information database, as of September 2014. Most of these products are under investigation in in vitro or in vivo trials. Among them, Garcinia mangostana Linn. (mangosteen) is a tropical fruit native to Southeast Asia, and a-mangostin is the most abundant xanthone (Table 1) in mangosteen pericarp. In mice fed a-mangostin in vivo, the volume of subcutaneous tumors of CRC has been demonstrated to be significantly smaller than that observed in mice fed a control diet, and xanthones and their metabolites have been identified in the serum, tumors, the liver and feces [57]. Next, in order to develop more efficacious Wnt inhibitors than naturally occurring stilbene derivatives (Table 1), Zhang et al. synthesized and evaluated a panel of fluorinated resveratrol and pterostilbene derivatives [58] and verified the inhibitory effects of fluorinated N,N-dialkylaminostilbenes at nanomolar levels. Among flavones (Tables 2 and 5), luteolin [59] and fisetin [60] have also been investigated regarding their anti-cancer efficacy. In particular, tea catechins have recently received attention due to their possible effectiveness for cancer prevention. Among tea catechins, green tea catechins are the most frequently investigated with respect to their cancer-preventive properties, and an increasing number of studies have reported that EGCG is one of the most potent catechins, capable of inhibiting cell

proliferation and inducing apoptosis in cancer cells [61]. In 2008, Yuan et al. reported that EGCG has preventive effects on preneoplastic lesions induced by 2-amino-3-methylimidazo[4,5-f ] quinoline in mice [62]. Among lignans (Tables 1 and 5), honokiol [65], magnolol [66], podophyllotoxin, silibinin and hydnocarpin have been evaluated in terms of their capacity for cancer prevention and anti-cancer efficacy. As shown in Table 5, substances other than polyphenols have also been investigated. Among alkaloids, the phenanthroindolizidine alkaloid antofine was found to inhibit cell growth and potentiate TNF-a-induced apoptosis in human colon cancer cells [67]. Among terpenes, maslinic acid is a natural hydroxyl pentacyclic derivative originating from pressed olives (Olea europaea Linn.). Reyes-Zurita et al. found that maslinic acid induces apoptosis in HT29 colon cancer cells via the mitochondrial apoptotic pathway [69]. Furthermore, NPs with other structures, such as polyacetylenes and polyenes [72], chromane derivatives [73], grifolin [74], g-oryzanol [75], yuanhuacine [76], chartreusin [77] and statins [78], have been explored for the purpose of drug discovery for CRC (Table 5). In addition, NPs derived from organisms in marine environments have recently been investigated. For example, TPU942 and its derivatives are substances isolated from a


11

K. Miura et al.

marine-derived fungus, Beauveria bassiana [79], some of which inhibit cell growth against HCT-15 colon and other cancer cells. As listed in Table 5, in addition to purified substances, crude extracts of apple [80,81], American ginseng (Panax quinquefolius Linn.), black raspberry [82] and others have also been studied. In 2013, Gonza´lez-Vallinas et al. reported the dose-dependent anti-tumor activities of rosemary extract, with a synergistic effect in combination with 5-FU, in colon cancer cells [83].


8.

Conclusion

In short conclusion, NPs are evolutionarily designed and contain more complex and challenging structures than synthetic compounds, and they have recently received renewed focus as a rich repository for drug discovery. Irinotecan as a camptothecin derivative has been widely used in standard regimens for mCRC, and other derivatives of camptothecin are under investigation in preclinical studies. A variety of NPs, including curcumin, talaporfin sodium, EPA, resveratrol and bioflavonoids, are currently being assessed in clinical trials of CRC, and other NPs derived as purified ingredients and crude extracts are also under investigation for drug discovery. 9.

Expert opinion

In order to promote the discovery of anti-cancer agents using NPs, new technologies should be further applied, some of which have been utilized for the development of targeted agents. These technologies include the cultivation of drugproducing organisms, extraction and purification of substances, optimization of lead structures, appreciation of targets, utilization of genomics information as well as bioinformatics and cheminformatics with in silico analyses, large-scale production of drug candidates and libraries, annotation of biosynthetic pathways, drug delivery in the host and tumors and others. For example, when culturing microbes under standardized laboratory conditions, biosynthesis genes may remain silent and valuable substances may be overlooked. Scherlach and Hertweck reviewed strategies to yield such cryptic NPs via external cues in addition to co-cultivation and genomic approaches, epigenetic remodeling and engineered pathway activation [84]. In terms of the synthesis of anti-cancer agents, NPs often contain particularly challenging structures. Recently, chemists have begun utilizing NPs for the development of asymmetric catalysis according to enantioselective methods, as shown by Mohr et al. [85]. In 2014, Morrison and Hergenrother reviewed the use of NPs as starting points for the generation of complex compounds [86]. Furthermore, Kirschning and Hahn explored the synthetic processes required to merge chemical synthesis and biosynthesis for the development of NPs and NP libraries [87]. The utilization of NPs for the construction of NP-like synthetic libraries has also been discussed [88]. In addition to their roles as drugs, NPs have been successfully used as molecular probes 12

to identify disease relevant targets [89]. Further advances in systemic biology are expected to support the creation of large and reliable libraries of pure NPs for drug discovery [90] as well as cost-effective microbial production processes for developing complex NPs [91]. In fact, systems biology contributes to our understanding of NPs with respect to their metabolism, expression and regulatory networks. On the other hand, synthetic biology approaches may benefit from utilizing plant and bacterial ‘omics’ as a source for the design and development of biological modules [92]. Regarding bioinformatics and cheminformatics, in order to further utilize information concerning NPs efficiently, Over et al. fragmented and analyzed data for > 180,000 structures derived from NPs to arrive at 2000 clusters of NP-derived fragments with high structural diversity [93], which was indeed useful for discovering novel ligands and inhibitors. Furthermore, a large-scale supercomputing platform is anticipated to be utilized for drug discovery using NPs in the future [94]. NPs are evolutionarily designed, chemically distinct from most synthetic compounds and contain challenging structures. Statistically, 40% of NPs are not represented by synthetic compounds [11]. As discussed earlier, new technologies for targeted agents should be utilized for drug discovery with NPs. In addition, although NPs have long been analyzed, it is estimated that < 15% of higher plants have been systematically investigated for the presence of bioactive compounds [16]. Despite the preparation of large-scale chemical libraries among pharmaceutical companies (containing 106 -- 107 molecules), investigators have begun to realize that they have captured only a tiny fraction of chemically diverse compounds; there are thought to be > 1060 possible organic structures with a molecular mass of < 400 Da. [95]. This means that there is certainly room to further explore these issues, using NPs derived from plants as well as other organisms. NPs derived from plants have been studied widely for centuries, whereas NPs originating from other organisms, especially those derived from marine organisms, have received attention only recently [96]. NPs derived from different organisms are estimated to have different properties based on their chemical structures and biological functions. For example, in the deep sea, no light penetrates and vision is less important [97]. In addition, other conditions in the deep sea, such as water pressure, pH and the water flow, are quite different from those noted in shallow water. Hence, NPs originating from the deep sea may have distinct properties. On the other hand, tissue samples from such organisms are difficult to collect on a large scale and may be challenging to cultivate. Therefore, the gene expression levels in the materials may be undetectable and valuable NPs may be overlooked. In addition, substances of interest initially found in these organisms may derive from extrinsic or symbiotic microorganisms. Nevertheless, a high proportion of deep-sea NPs are estimated to have cytotoxic effects against human cancer cells [97].




Recent studies support the hypothesis that NPs designed to interact with particular proteins may coincidentally bind with high affinity to other proteins of interest as therapeutic targets [10]. However, in a study by Dancı´k et al., using a computational approach and bioinformatics, the results implied that NPs may not display adequate versatility to be suitable for the treatment of all heritable human diseases, and small molecules are instead required to generate treatments targeting the root causes of disease [98]. Against this background, synthetic compounds may be more suitable for treating diseases than NPs. It is thus necessary to clarify how the properties of NPs and synthetic compounds differ. Despite the prolonged survival achieved with current chemotherapy regimens for mCRC, it remains difficult to cure patients with this disease. In order to obtain better therapeutic outcomes, the discovery of anti-cancer agents using NPs is required, and novel technologies must be utilized. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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For this purpose, understanding the molecular mechanisms of the carcinogenesis, progression and metastasis of CRC is essential, including the Wnt signaling and EGFR-RAS-RAFMAPK-MEK-ERK pathways, DNA mismatch repair, angiogenesis and other processes. This information must be comprehensively understood and combined with appropriate strategies for drug discovery.

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Affiliation

Koh Miura†1, Masayuki Satoh2, Makoto Kinouchi2, Kuniharu Yamamoto2, Yasuhiro Hasegawa2, Yoichiro Kakugawa2, Masaaki Kawai2, Kiyoshi Uchimi3, Hiroki Aizawa3, Shinobu Ohnuma4, Taiki Kajiwara4, Hiroto Sakurai2 & Tsuneaki Fujiya2 † Author for correspondence 1 Surgeon-in-Chief, Miyagi Cancer Center, Department of Surgery, 47-1 Nodayama, Natori 981-1293, Japan Tel: +81 22 384 3151; Fax: +81 22 381 1168; E-mail: [email protected] 2 Miyagi Cancer Center, Department of Surgery, 47-1 Nodayama, Natori 981-1293, Japan 3 Miyagi Cancer Center, Department of Gastroenterology, 47-1 Nodayama, Natori 981-1293, Japan 4 Tohoku University Graduate School of Medicine, Department of Surgery, 1-1 Seiryo-machi, Sendai 980-8574, Japan

Pharmacognosy: Science of natural products in drug discovery.

A historical overview of natural products in drug discovery.

A New Golden Age of Natural Products Drug Discovery.

Insights into drug discovery from natural products through structural modification.

New natural products as new leads for antibacterial drug discovery.

The re-emergence of natural products for drug discovery in the genomics era.

Alzheimer's disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes.

The use of natural products to target cancer stem cells.

Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs.

Preparative chromatography and natural products discovery.

"Pruning of biomolecules and natural products (PBNP)": an innovative paradigm in drug discovery.

Natural products and drug discovery: a survey of stakeholders in industry and academia.

An introduction to the special issue on pharmaceuticals, drug discovery and natural products.

Something old, something new: revisiting natural products in antibiotic drug discovery.

Overcome Cancer Cell Drug Resistance Using Natural Products.

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents.

Dereplication: racing to speed up the natural products discovery process.

System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.

Culture-independent discovery of natural products from soil metagenomes.

Direct Capture Technologies for Genomics-Guided Discovery of Natural Products.

Genome-guided discovery of diverse natural products from Burkholderia sp.

Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes.

The combined use of alphavirus replicons and pseudoinfectious particles for the discovery of antivirals derived from natural products.

Special issue in honor of William Fenical, a pioneer in marine natural products discovery and drug development.