- Email: [email protected]
Use of cancer chemopreventive phytochemicals as antineoplastic agents
Essay
Use of cancer chemopreventive phytochemicals as antineoplastic agents Maurizio D’Incalci, William P Steward, Andreas J Gescher
A lot of information has been gathered on cellular mechanisms by which chemopreventive phytochemicals, such as curcumin (a spice in curry) or epigallocatechin gallate (extracted from tea), interfere with carcinogenesis. A comparison of this knowledge with what we know about molecularly targeted chemotherapeutic agents suggests that it might be worthwhile to investigate the usefulness of such phytochemicals in the treatment of established malignant diseases. Phytochemicals use a plethora of antisurvival mechanisms, boost the host’s antiinflammatory defence, and sensitise malignant cells to cytotoxic agents. The restricted systemic availability of agents such as curcumin and epigallocatechin gallate, needs to be taken into account if they are to be developed as cochemotherapeutic drugs.
Introduction An abundance of mechanistic information has become available on how phytochemicals derived from dietary sources (figure 1), which have putative chemopreventive properties, interfere with tumour promotion and progression.1 Some of the mechanisms used by these agents—eg, modulation of oncogenic kinases or cell-cycle regulatory molecules—are identical to those through which molecularly targeted chemotherapeutic agents exert their activity.2 Therefore, chemopreventive phytochemicals could in theory serve as alternatives to chemically designed antineoplastic agents, as constituents of therapeutic drug combinations in advanced disease, or as adjuvant treatments. This argument makes economic sense because the costs associated with the generation or isolation and development of phytochemicals might well be lower than those associated with the discovery and development of new chemical entities. In this essay, we discuss the hypothesis that phytochemicals suspected to prevent cancer can also have a role in the treatment of neoplastic conditions and consider issues such as the mechanisms which these agents share with chemotherapeutic agents, their pharmacokinetic properties, and their potential clinical development. The polyphenols curcumin, epigallocatechin gallate, resveratrol, and indole-3-carbinol serve as examples of a wide variety of naturally occurring phytochemicals with proven or suspected chemopreventive activity (figure 2).
tumour growth, and attainment of ability to invade and metastasise.3 Some chemopreventive phytochemicals can interfere with the survival of malignant cells by hitting targets germane to the hallmarks of cancer. This interference means that some of the mechanisms that these agents use, might mediate not only the prevention of oncogenic events but also their reversal.
Lancet Oncol 2005; 6: 899–904 Pharmacological Research Institute Mario Negri, Milan, Italy (M D’Incalci MD) and Department of Cancer Studies, University of Leicester, Leicester, UK (Prof W P Steward MD, Prof A J Gescher DSc) Correspondence to: Prof Andreas Gescher, Department of Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK [email protected]
Chemotherapeutic mechanisms Analogous to molecularly targeted chemotherapeutic drugs, chemopreventive phytochemicals confound events in host and tumour tissue that sustain the hallmarks of cancer—acquisition of selfsufficiency in growth signals, insensitivity to signals that usually inhibit proliferation, use of survival pathways to avoid the apoptosis that can occur in irreversibly damaged cells, the ability to replicate indefinitely, initiation of angiogenesis to ensure sufficient oxygen and nutrient supply to sustain http://oncology.thelancet.com Vol 6 November 2005
Figure 1: The chemopreventive phytochemical resveratrol is formed in the skin of black grapes
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Curcumin H O
O
CH30
OCH3
OH
HO Epigallocatechin gallate OH OH HO
O O
OH OH
O OH OH OH Resveratrol OH
HO OH Indole-3-carbinol OH
N H
Figure 2: Structures of curcumin from rhizomes of curcuma, epigallocatechin gallate from green-tea leaves, resveratrol from black grapes, and indole-3-carbinol from cabbage and sprouts
These phytochemicals have many molecular targets and are therefore non-specific. Thus, they are dissimilar to molecularly targeted chemotherapeutic agents that are designed to hit only one, or very few, specific targets. This pleiotropism might constitute an advantage, because a complicated disease, such as cancer, is sustained by many oncogenic (ie, functionally dysregulated) events.
Confounding of cell growth and survival The growth-inhibitory and apoptosis inducing properties of curcumin, resveratrol, epigallocatechin gallate, and indole-3-carbinol have been well documented. Here, we discuss a few examples of mechanisms by which these agents are thought to compromise cancer-cell survival (figure 3). These mechanisms operate in a cell-specific fashion and frequently only within a narrow concentration window. 900
Curcumin4 and resveratrol5 can induce apoptosis by upregulation of the proapoptotic proto-oncogenes BAX and BAK, which results in the release of cytochrome c from the mitochondria and activation of various caspases. Induction of apoptosis by curcumin has also been linked to phosphorylation and activation of C-JUN terminal kinase.6 Curcumin arrested coloncancer cells in the G2/M phase of the cell cycle and caused them to undergo apoptosis via impairment of cell adhesion and Wingless signalling, pathways that are thought to drive colorectal cancer.7 Curcumin has also been shown to suppress expression of the cyclin D1 gene and of epidermal growth factor receptor (EGFR) via activation of peroxisome proliferatoractivated receptor- (PPAR).8 Antiangiogenic properties of curcumin can be seen in umbilical vein endothelial cells. In these cells, curcumin induces G0/G1 or G2/M phase cell-cycle arrest by upregulation of the tumour suppressor P53 and the cyclindependent kinase inhibitors P21 and P27.9 Both curcumin10 and resveratrol11 suppress activation of nuclear factorB (NFB) and gene expression regulated by NFB. Compromised survival of various types of cancer cells by resveratrol has been consistently associated with arrest of cells in S phase of the cell cycle and decrease of cyclin B1 expression.12 Epigallocatechin gallate arrested epidermoid carcinoma cells in the G0/G1 phase and induced apoptosis accompanied by upregulation of cyclin-dependent kinase inhibitors, downregulation of cyclin D1, cyclindependent kinase 4, cyclin dependent kinase 6, and inhibition of NFB.13 Induction of apoptosis in humanderived breast-cancer cells or prostate-cancer cells by indole-3-carbinol has been associated with upregulation of BAX and cyclin-dependent kinase inhibitors, downregulation of the antiapoptotic genes BCL2, CDK6, and NFB,14 and inhibition of phosphorylation, and thus activation, of AKT1.15 P53, NFB, AKT, PPAR, and cyclin-dependent kinase inhibitors are among the very mechanistic targets of the chemotherapeutic drugs trastuzumab, cetuximab, gefitinib, erlotinib, and imatinib. They modulate such targets via effects on upstream proteins that are relevant to cancer.16 The antibodies (trastuzumab; antihuman EGFR2, cetuximab; antiEGFR) recognise cell-surface receptors crucial for survival signalling, and the small molecules (gefitinib and erlotinib both directed at EGFR, and imatinib directed at BCR-ABL1) target kinase domains of the receptors and other oncogenic protein tyrosine kinases, which, in turn, can suppress AKT activation. Epigallocatechin gallate strongly and directly inhibited telomerase,17 an enzyme essential for unlocking the proliferative capacity of cancer cells by maintenance of the tips of their chromosomes. Classic anticancer drug mechanisms such as inhibition of dihydrofolate reductase18 and inhibition of DNA http://oncology.thelancet.com Vol 6 November 2005
Essay
methylation19 have also been suggested for epigallocatechin gallate. Indole-3-carbinol also has antioestrogenic properties20 and resembles tamoxifen.
cological agents in their own right, which exert activity at concentrations far exceeding those reached by dietary intake.
Anti-inflammatory effects
Clinical pharmacology
Inflammatory stimuli, such as those triggered by the cycoloxygenase (COX) enzyme COX2, sustain carcinogenesis in tissues like the colorectum, breast, and lung. Reduction of inflammation has been discussed as a viable cancer chemotherapeutic mechanism—eg, for trabectedin.21 Curcumin and resveratrol can exert anti-inflammatory mechanisms, and their abilities to interfere with the inflammatory cascade mediated by eicosanoids, COX enzymes, and lipoxygenases and to inhibit NFB activation have been implicated as mechanisms. Non-steroidal anti-inflammatory drugs are thought to prevent colon cancer by inhibition of COX enzymes, especially COX2. Curcumin and resveratrol affect COX2 in that they can downregulate its transcription,22,23 and thus decrease the amount of enzyme available for the catalytic generation of prostaglandins.
Many chemopreventive phytochemicals are polyphenols. By their very nature, phenols are prone to undergo metabolic conjugation, and such conjugates are almost invariably devoid of pharmacological activity. Ample data on the pharmacokinetics of these polyphenols in animals suggest that they have varying degrees of restricted systemic availability, probably related, at least partly, to their avid metabolic disposition. Poor bioavailability has been shown for curcumin,37–39 resveratrol,40,41 and epigallocatechin gallate 42,43 in human beings. Indole-3-carbinol is unstable in the biophase, as it undergoes a complicated series of spontaneous and enzyme-catalyzed polymerisations, which compromise its bioavailability, in analogy to the polyphenols.44 Thousands of polyphenolic flavonoids are found as glycosides in the plant kingdom. Therefore, a systematic search might uncover cogeners with tumour-suppressive properties and pharmaceutical properties that are better than those of resveratrol and curcumin.
Chemosensitising effects Several studies have documented the ability of chemopreventive phytochemicals to increase the sensitivity of cancer cells to conventional anticancer drugs. Indole-3carbinol,24,25 curcumin,26–29 epigallocatechin gallate,30–32 and resveratrol33 counteract drug resistance mediated by multidrug resistance protein or multidrug resistancerelated protein in various cancer cells in vitro. Information on sensitisation in animals in vivo is much less abundant, but it has been shown for indole-3carbinol and epigallocatechin gallate, which increased sensitivity of malignant growth towards doxorubicin in nude mice.34,35 Phytochemicals might be useful to both increase the activity of chemotherapy agents and ameliorate toxic effects of these agents to the host. Indole-3-carbinol has been shown to abrogate the hepatotoxicity associated with trabectedin in rats,36 pinpointing a rescue strategy worthy of investigation in human beings. The mechanism of this antidote activity remains unresolved, though metabolic detoxification of trebectedin might contribute to protection.
Whole-diet matrix versus isolated phytochemicals The doses at which phytochemicals are ingested with the diet are, in general, orders of magnitude below those needed to give pharmacologically active concentrations. Therefore, diet-derived phytochemicals need to be considered from two viewpoints: first, in their role as actual dietary constituents, in which they might exert pharmacological actions at very low concentrations together with many other food ingredients with the involvement of potentially synergistic or antagonistic interactions, and second as pharmahttp://oncology.thelancet.com Vol 6 November 2005
JNK Wnt signalling NFB Curcumin
PPAR␥ Cyclin D1 P53
G2
CIPs
M
Apoptosis
G1 S
Cyclin D1
NFB Cyclin B1
CIPs
Resveratrol Epigallocatechin gallate
Apoptosis
CDK 4/6 NFB Apoptosis
Akt CDK 6 CIPs
Indole-3-carbinol
NFB Apoptosis
Figure 3: Mechanistic targets germane to cell survival affected by chemopreventive phytochemicals as reported in in-vitro experiments CDK=cyclin-dependent kinase, CIP=CDK inhibitor, JNK=c jun kinase, NFB=nuclear factor B, PPAR=peroxisome proliferator-activated receptor, ↓=decrease or inhibition; ↑=increase or induction ⊥=inhibition.
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Phytochemicals in combination treatment
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Treatment of malignant diseases with a combination of a suitable chemopreventive phytochemical and an established anticancer agent might be a realistic and promising option. Additive or synergistic actions of chemopreventive phytochemicals have been recorded (eg, epigallocatechin gallate substantially enhanced the growth-inhibitory effects of fluorouracil in head and neck squamous carcinoma cells at concentrations that have been found in serum after oral administration).45 But interactions could also be unfavourable. Curcumin has been shown to inhibit apoptosis induced by chemotherapeutic drugs in human breast-cancer cell lines and in a tumour xenograft model dietary supplementation with curcumin.46 The investigators postulated that curcumin decreased the extent of apoptosis induced by cyclophosphamide46 by stopping formation of reactive oxygen species and JNK activation, and that exposure to curcumin might therefore be detrimental to chemotherapy in some cases. A diet enriched with a low dose of soya isoflavones abrogated prevention of mammary tumours by tamoxifen in the wild-type ERBB2 transgenic mouse.47 These examples show that because they have many targets, phytochemicals could antagonise the beneficial effects of coadministered drugs. The possibility that such antagonism might occur and compromise the rationale for a particular combination needs to be investigated in experiments in vitro and in vivo before combinations are assessed in the clinic.
a cogent case for a new approach to be applied to the development of agents, which might have activity against established disease, be effective as chemopreventives, or have a dual role. Modulation of the mechanistic targets shown in figure 3 requires the presence of chemopreventive phytochemicals at concentrations in the 10–50 mol/L range (as discussed for resveratrol49). That these agents have poor systemic availability renders such concentrations difficult to achieve in the whole organism. By contrast, much of the phytochemical could be excreted mostly unchanged to generate abundant concentrations in the gastrointestinal tract, whereas this dose might be insufficient to give systemic concentrations in the mol/L range. This property might be particularly advantageous for treatment of malignant disease in the gastrointestinal tract by use of agents such as curcumin and resveratrol, which have been shown to perturb oncogenic mechanisms in the colorectum. If these agents are to be investigated in the treatment of malignant diseases such as prostate cancer, they would need to be transported via the systemic circulation to the target organ—proof-of-concept studies are needed to show that the agent reaches the target organ in amounts sufficient to elicit activity as indicated in in-vitro experiments. Green-tea polyphenols, including epigallocatechin gallate, are not effective treatments against prostate cancer when given as monotherapy,50 but this trial did not include a quantitative assessment of polyphenols in the target tissue. Thus, it might not have reached the prostate in bioactive concentrations.
Phytochemical drug development
Conclusions
When chemopreventive phytochemicals are considered for use within a defined chemotherapeutic framework, their antineoplastic effects need to be checked in suitable animal models and ultimately in pharmacokinetic and pharmacodynamic pilot studies in human beings. The long-term experience, that we have of phytochemicals as diet constituents, suggest that they do not elicit adverse effects in human beings. Nevertheless, their safety needs utmost scrutiny, because the doses at which they are to be used will probably grossly exceed those at which they are ingested with the diet. Pilot phase I studies with suitable pharmacodynamic endpoints (or surrogate endpoints) should be designed in human beings to investigate whether the phytochemical exerts much the same activity as that seen in vitro and in vivo. Such pilot studies could be done in patients with cancer or in healthy volunteers. An especially attractive pilot experimental strategy involves the presurgery model, which allows surgical removal of tissue after patients have ingested the agent under investigation. An example of this approach is the use of curcumin in patients undergoing colectomy.38 Abbruzzese and Lippman48 have argued that cancer chemoprevention and chemotherapy should converge in clinical phase-I testing. They present
Clinical experience with the EGFR tyrosine kinase inhibitors suggests that the molecular signature of a tumour determines its susceptibility towards the effects of molecular targeted drugs,51 suggesting that oncologists will eventually want to use a range of agents capable of interfering with neoplastic cell survival in diverse ways counteracting the corollary of the different bespoke molecular signatures driving the malignant diseases. In view of the evidence emerging from studies of the mechanisms of action of chemopreventive phytochemicals (figure 3), we think that some phytochemicals at safe doses can complement new molecularly targeted or traditional anticancer drugs in counteracting the survival of malignant cells. Nevertheless, these agents tend to have low bioavailability, and the mechanisms they engage could comprise elements that antagonise, rather than augment, some activities of coadministered drugs. Therefore, more work is needed, both in terms of elucidation of primary mechanisms and discovery of new molecules, to help support or refute the hypothesis that some chemopreventive phytochemicals might be valuable in the treatment of established malignant disease. http://oncology.thelancet.com Vol 6 November 2005
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The thousands of flavonoids in the plant kingdom offer huge opportunity for agent discovery. Antineoplastic activity of chemopreventive phytochemicals in human beings will probably be difficult to show, time consuming, and expensive, the latter point being especially pertinent as powerful industrial support for these agents does not, in general, exist. This does not mean that it would not be a worthwhile undertaking. The reward could be considerable. Conflict of interest We declare no conflicts of interest. Acknowledgment We thank Stefania Filippeschi and Sue Spriggs for help with the references and the UK Medical Research Council, the US National Cancer Institute Chemoprevention Branch, and the Italian Association for Cancer Research for research support and sponsorship. References 1 Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003; 3: 768–80. 2 Dorai T, Aggarwal BB. Role of chemopreventive agents in cancer therapy. Cancer Lett 2004; 215: 129–40. 3 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 4 Pal S, Choudhuri T, Chattopadhyay S, et al. Mechanisms of curcumin-induced apoptosis of Ehrlich’s ascites carcinoma cells. Biochem Biophys Res Commun 2001; 288: 658–65. 5 Delmas D, Rebe C, Lacour S, et al. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J Biol Chem 2003; 278: 41482–90. 6 Collett GP, Campbell FC. Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 2004; 25: 2183–89. 7 Jaiswal AS, Marlow BP, Gupta N, Narayan S. -catenin-mediated transactivation and cell—cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002; 21: 8414–27. 8 Chen A, Xu J. Activation of PPAR- by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol Gastrointest Liver Physiol 2005; 288: G447–56. 9 Park MJ, Kim EH, Park IC, et al. Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial (ECV304) cells by up-regulating cyclin-dependent kinase inhibitors, p21(WAF1/CIP1), p27(KIP1) and p53. Int J Oncol 2002; 21: 379–83. 10 Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal antiinflammatory agents differ in their ability to suppress NF-kappa B activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 2004; 23: 9247–58. 11 Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 2000; 164: 6509–19. 12 Joe AK, Liu H, Suzui M, et al. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res 2002; 8: 893–903. 13 Ahmad N, Gupta S, Mukhtar H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factorB in cancer cells versus normal cells. Arch Biochem Biophys 2000, 376: 338–46. 14 Sarkar FH, Rahman KMW, Li YW. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J Nutr 2003; 133 (suppl): S2434–39.
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Howells LM, Gallacher-Horley B, Houghton CE, et al. Indole-3carbinol inhibits protein kinase B/Akt and induces apoptosis in the human breast tumor cell line MDA MB468 but not in the nontumorigenic HBL100 line. Mol Cancer Ther 2002; 1: 1161–72. Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003; 3: 17–22. Naasani I, Seimiya H, Tsuruo T. Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins. Biochem Biophys Res Commun 1998; 249: 391–96. Navarro-Peran E, Cabezas-Herrera J, Garcia-Canovas F, et al. The antifolate activity of tea catechins. Cancer Res 2005; 65: 2059–64. Fang MZ, Wang YM, Ai N.et al. Tea polyphenol (-)epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 2003; 63: 7563–70. Auborn KJ, Fan S, Rosen EM, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr 2003, 133 (suppl): S2470–75. Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res 2005; 65: 2964–71. Plummer SM, Holloway KA, Manson MM, et al. Inhibition of cyclooxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NFkappaB activation via the NIK/IKK signalling complex. Oncogene 1999; 18: 6013–20. Subbaramaiah K, Chung WJ, Michaluart P, et al. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 1998; 273: 21875–82. Arora A, Seth K, Kalra N, Shukla Y. Modulation of Pglycoprotein-mediated multidrug resistance in K562 leukemic cells by indole-3-carbinol. Toxicol Appl Pharmacol 2005; 202: 237–43. Arora A, Shukla Y. Modulation of vinca alkaloid induced P-glycoprotein expression by indole-3-carbinol. Cancer Lett 2003; 189: 167–73. Chearwae W, Anuchapreeda S, Nandigama K, et al. Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II and III purified from turmeric powder. Biochem Pharmacol 2004, 68: 2043–52. Limtrakul P, Anuchapreeda S, Buddhasukh D. Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. BMC Cancer 2004; 4: 13. Romiti N, Tongiani R, Cervelli F, Chieli E. Effects of curcumin on P-glycoprotein in primary cultures of rat hepatocytes. Life Sci 1998; 62: 2349–58. Wortelboer HM, Usta M, Van der Velde AE, et al. Interplay between MRP inhibition and metabolism of MRP inhibitors: the case of curcumin. Chem Res Toxicol 2003, 16: 1642–51. Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 2002; 1542: 149–59. Sadzuka Y, Sugiyama T, Sonobe T. Efficacies of tea components on doxorubicin induced antitumour activity and reversal of multidrug resistance. Toxicol Lett 2000; 114: 155–62. Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol 2004; 56: 1307–14. Nabekura T, Kamiyama S, Kitagawa S. Effects of dietary chemopreventive phytochemicals on P-glycoprotein function. Biochem Biophys Res Commun 2005; 327: 866–70. Christensen JG, LeBlanc GA. Reversal of multidrug resistance in vivo by dietary administration of the phytochemical indole-3carbinol. Cancer Res 1996; 56: 574–81. Zhang Q, Wei D, Liu J. In vivo reversal of doxorubicin resistance by (-)-epigallocatechin gallate in a solid human carcinoma xenograft. Cancer Lett 2004; 208: 179–86. Donald S, Verschoyle RD, Greaves P, et al. Dietary agent indole3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. Int J Cancer 2004; 111: 961–67.
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Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 2004; 10: 6847–54. Garcea G, Berry DP, Jones DJL, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev 2005; 14: 120–25. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or premalignant lesions. Anticancer Res 2001; 21: 2895–900. Goldberg DA, Yan J, Soleas GJ. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem 2003; 36: 79–87. Walle T, Hsieh F, DeLegge MH, et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 2004; 32: 1377–82. Ullmann U, Haller J, Decourt JP, et al. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J Int Med Res 2003; 31: 88–101. Chow HHS, Cai Y, Hakim IA, et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 2003; 9: 3312–19. Anderton MJ, Manson MM, Verschoyle RD, et al. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res 2004; 10: 5233–41.
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Masuda M, Suzui M, Weinstein IB. Effects of epigallocatechin-3gallate on growth, epidermal growth factor receptor signaling pathways, gene expression and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res 2001, 7: 4220–29. Somasundaram S, Edmund NA, Moore DT, et al. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 2002, 62: 3868–75. Liu B, Edgerton S, Yang X, et al. Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res 2005; 65: 879–86. Abbruzzese JL, Lippman SM. The convergence of cancer prevention and therapy in early-phase clinical drug development. Cancer Cell 2004; 6: 321–26. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomarkers Prev 2003; 12: 953–57. Jatoi A, Ellison N, Burch PA, et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer 2003; 97: 1442–46. Chabner BA. The miracle of Iressa. Oncologist 2004; 9: 245–46.
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Use of cancer chemopreventive phytochemicals as antineoplastic agents Maurizio D’Incalci, William P Steward, Andreas J Gescher
A lot of information has been gathered on cellular mechanisms by which chemopreventive phytochemicals, such as curcumin (a spice in curry) or epigallocatechin gallate (extracted from tea), interfere with carcinogenesis. A comparison of this knowledge with what we know about molecularly targeted chemotherapeutic agents suggests that it might be worthwhile to investigate the usefulness of such phytochemicals in the treatment of established malignant diseases. Phytochemicals use a plethora of antisurvival mechanisms, boost the host’s antiinflammatory defence, and sensitise malignant cells to cytotoxic agents. The restricted systemic availability of agents such as curcumin and epigallocatechin gallate, needs to be taken into account if they are to be developed as cochemotherapeutic drugs.
Introduction An abundance of mechanistic information has become available on how phytochemicals derived from dietary sources (figure 1), which have putative chemopreventive properties, interfere with tumour promotion and progression.1 Some of the mechanisms used by these agents—eg, modulation of oncogenic kinases or cell-cycle regulatory molecules—are identical to those through which molecularly targeted chemotherapeutic agents exert their activity.2 Therefore, chemopreventive phytochemicals could in theory serve as alternatives to chemically designed antineoplastic agents, as constituents of therapeutic drug combinations in advanced disease, or as adjuvant treatments. This argument makes economic sense because the costs associated with the generation or isolation and development of phytochemicals might well be lower than those associated with the discovery and development of new chemical entities. In this essay, we discuss the hypothesis that phytochemicals suspected to prevent cancer can also have a role in the treatment of neoplastic conditions and consider issues such as the mechanisms which these agents share with chemotherapeutic agents, their pharmacokinetic properties, and their potential clinical development. The polyphenols curcumin, epigallocatechin gallate, resveratrol, and indole-3-carbinol serve as examples of a wide variety of naturally occurring phytochemicals with proven or suspected chemopreventive activity (figure 2).
tumour growth, and attainment of ability to invade and metastasise.3 Some chemopreventive phytochemicals can interfere with the survival of malignant cells by hitting targets germane to the hallmarks of cancer. This interference means that some of the mechanisms that these agents use, might mediate not only the prevention of oncogenic events but also their reversal.
Lancet Oncol 2005; 6: 899–904 Pharmacological Research Institute Mario Negri, Milan, Italy (M D’Incalci MD) and Department of Cancer Studies, University of Leicester, Leicester, UK (Prof W P Steward MD, Prof A J Gescher DSc) Correspondence to: Prof Andreas Gescher, Department of Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK [email protected]
Chemotherapeutic mechanisms Analogous to molecularly targeted chemotherapeutic drugs, chemopreventive phytochemicals confound events in host and tumour tissue that sustain the hallmarks of cancer—acquisition of selfsufficiency in growth signals, insensitivity to signals that usually inhibit proliferation, use of survival pathways to avoid the apoptosis that can occur in irreversibly damaged cells, the ability to replicate indefinitely, initiation of angiogenesis to ensure sufficient oxygen and nutrient supply to sustain http://oncology.thelancet.com Vol 6 November 2005
Figure 1: The chemopreventive phytochemical resveratrol is formed in the skin of black grapes
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Curcumin H O
O
CH30
OCH3
OH
HO Epigallocatechin gallate OH OH HO
O O
OH OH
O OH OH OH Resveratrol OH
HO OH Indole-3-carbinol OH
N H
Figure 2: Structures of curcumin from rhizomes of curcuma, epigallocatechin gallate from green-tea leaves, resveratrol from black grapes, and indole-3-carbinol from cabbage and sprouts
These phytochemicals have many molecular targets and are therefore non-specific. Thus, they are dissimilar to molecularly targeted chemotherapeutic agents that are designed to hit only one, or very few, specific targets. This pleiotropism might constitute an advantage, because a complicated disease, such as cancer, is sustained by many oncogenic (ie, functionally dysregulated) events.
Confounding of cell growth and survival The growth-inhibitory and apoptosis inducing properties of curcumin, resveratrol, epigallocatechin gallate, and indole-3-carbinol have been well documented. Here, we discuss a few examples of mechanisms by which these agents are thought to compromise cancer-cell survival (figure 3). These mechanisms operate in a cell-specific fashion and frequently only within a narrow concentration window. 900
Curcumin4 and resveratrol5 can induce apoptosis by upregulation of the proapoptotic proto-oncogenes BAX and BAK, which results in the release of cytochrome c from the mitochondria and activation of various caspases. Induction of apoptosis by curcumin has also been linked to phosphorylation and activation of C-JUN terminal kinase.6 Curcumin arrested coloncancer cells in the G2/M phase of the cell cycle and caused them to undergo apoptosis via impairment of cell adhesion and Wingless signalling, pathways that are thought to drive colorectal cancer.7 Curcumin has also been shown to suppress expression of the cyclin D1 gene and of epidermal growth factor receptor (EGFR) via activation of peroxisome proliferatoractivated receptor- (PPAR).8 Antiangiogenic properties of curcumin can be seen in umbilical vein endothelial cells. In these cells, curcumin induces G0/G1 or G2/M phase cell-cycle arrest by upregulation of the tumour suppressor P53 and the cyclindependent kinase inhibitors P21 and P27.9 Both curcumin10 and resveratrol11 suppress activation of nuclear factorB (NFB) and gene expression regulated by NFB. Compromised survival of various types of cancer cells by resveratrol has been consistently associated with arrest of cells in S phase of the cell cycle and decrease of cyclin B1 expression.12 Epigallocatechin gallate arrested epidermoid carcinoma cells in the G0/G1 phase and induced apoptosis accompanied by upregulation of cyclin-dependent kinase inhibitors, downregulation of cyclin D1, cyclindependent kinase 4, cyclin dependent kinase 6, and inhibition of NFB.13 Induction of apoptosis in humanderived breast-cancer cells or prostate-cancer cells by indole-3-carbinol has been associated with upregulation of BAX and cyclin-dependent kinase inhibitors, downregulation of the antiapoptotic genes BCL2, CDK6, and NFB,14 and inhibition of phosphorylation, and thus activation, of AKT1.15 P53, NFB, AKT, PPAR, and cyclin-dependent kinase inhibitors are among the very mechanistic targets of the chemotherapeutic drugs trastuzumab, cetuximab, gefitinib, erlotinib, and imatinib. They modulate such targets via effects on upstream proteins that are relevant to cancer.16 The antibodies (trastuzumab; antihuman EGFR2, cetuximab; antiEGFR) recognise cell-surface receptors crucial for survival signalling, and the small molecules (gefitinib and erlotinib both directed at EGFR, and imatinib directed at BCR-ABL1) target kinase domains of the receptors and other oncogenic protein tyrosine kinases, which, in turn, can suppress AKT activation. Epigallocatechin gallate strongly and directly inhibited telomerase,17 an enzyme essential for unlocking the proliferative capacity of cancer cells by maintenance of the tips of their chromosomes. Classic anticancer drug mechanisms such as inhibition of dihydrofolate reductase18 and inhibition of DNA http://oncology.thelancet.com Vol 6 November 2005
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methylation19 have also been suggested for epigallocatechin gallate. Indole-3-carbinol also has antioestrogenic properties20 and resembles tamoxifen.
cological agents in their own right, which exert activity at concentrations far exceeding those reached by dietary intake.
Anti-inflammatory effects
Clinical pharmacology
Inflammatory stimuli, such as those triggered by the cycoloxygenase (COX) enzyme COX2, sustain carcinogenesis in tissues like the colorectum, breast, and lung. Reduction of inflammation has been discussed as a viable cancer chemotherapeutic mechanism—eg, for trabectedin.21 Curcumin and resveratrol can exert anti-inflammatory mechanisms, and their abilities to interfere with the inflammatory cascade mediated by eicosanoids, COX enzymes, and lipoxygenases and to inhibit NFB activation have been implicated as mechanisms. Non-steroidal anti-inflammatory drugs are thought to prevent colon cancer by inhibition of COX enzymes, especially COX2. Curcumin and resveratrol affect COX2 in that they can downregulate its transcription,22,23 and thus decrease the amount of enzyme available for the catalytic generation of prostaglandins.
Many chemopreventive phytochemicals are polyphenols. By their very nature, phenols are prone to undergo metabolic conjugation, and such conjugates are almost invariably devoid of pharmacological activity. Ample data on the pharmacokinetics of these polyphenols in animals suggest that they have varying degrees of restricted systemic availability, probably related, at least partly, to their avid metabolic disposition. Poor bioavailability has been shown for curcumin,37–39 resveratrol,40,41 and epigallocatechin gallate 42,43 in human beings. Indole-3-carbinol is unstable in the biophase, as it undergoes a complicated series of spontaneous and enzyme-catalyzed polymerisations, which compromise its bioavailability, in analogy to the polyphenols.44 Thousands of polyphenolic flavonoids are found as glycosides in the plant kingdom. Therefore, a systematic search might uncover cogeners with tumour-suppressive properties and pharmaceutical properties that are better than those of resveratrol and curcumin.
Chemosensitising effects Several studies have documented the ability of chemopreventive phytochemicals to increase the sensitivity of cancer cells to conventional anticancer drugs. Indole-3carbinol,24,25 curcumin,26–29 epigallocatechin gallate,30–32 and resveratrol33 counteract drug resistance mediated by multidrug resistance protein or multidrug resistancerelated protein in various cancer cells in vitro. Information on sensitisation in animals in vivo is much less abundant, but it has been shown for indole-3carbinol and epigallocatechin gallate, which increased sensitivity of malignant growth towards doxorubicin in nude mice.34,35 Phytochemicals might be useful to both increase the activity of chemotherapy agents and ameliorate toxic effects of these agents to the host. Indole-3-carbinol has been shown to abrogate the hepatotoxicity associated with trabectedin in rats,36 pinpointing a rescue strategy worthy of investigation in human beings. The mechanism of this antidote activity remains unresolved, though metabolic detoxification of trebectedin might contribute to protection.
Whole-diet matrix versus isolated phytochemicals The doses at which phytochemicals are ingested with the diet are, in general, orders of magnitude below those needed to give pharmacologically active concentrations. Therefore, diet-derived phytochemicals need to be considered from two viewpoints: first, in their role as actual dietary constituents, in which they might exert pharmacological actions at very low concentrations together with many other food ingredients with the involvement of potentially synergistic or antagonistic interactions, and second as pharmahttp://oncology.thelancet.com Vol 6 November 2005
JNK Wnt signalling NFB Curcumin
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Figure 3: Mechanistic targets germane to cell survival affected by chemopreventive phytochemicals as reported in in-vitro experiments CDK=cyclin-dependent kinase, CIP=CDK inhibitor, JNK=c jun kinase, NFB=nuclear factor B, PPAR=peroxisome proliferator-activated receptor, ↓=decrease or inhibition; ↑=increase or induction ⊥=inhibition.
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Phytochemicals in combination treatment
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Treatment of malignant diseases with a combination of a suitable chemopreventive phytochemical and an established anticancer agent might be a realistic and promising option. Additive or synergistic actions of chemopreventive phytochemicals have been recorded (eg, epigallocatechin gallate substantially enhanced the growth-inhibitory effects of fluorouracil in head and neck squamous carcinoma cells at concentrations that have been found in serum after oral administration).45 But interactions could also be unfavourable. Curcumin has been shown to inhibit apoptosis induced by chemotherapeutic drugs in human breast-cancer cell lines and in a tumour xenograft model dietary supplementation with curcumin.46 The investigators postulated that curcumin decreased the extent of apoptosis induced by cyclophosphamide46 by stopping formation of reactive oxygen species and JNK activation, and that exposure to curcumin might therefore be detrimental to chemotherapy in some cases. A diet enriched with a low dose of soya isoflavones abrogated prevention of mammary tumours by tamoxifen in the wild-type ERBB2 transgenic mouse.47 These examples show that because they have many targets, phytochemicals could antagonise the beneficial effects of coadministered drugs. The possibility that such antagonism might occur and compromise the rationale for a particular combination needs to be investigated in experiments in vitro and in vivo before combinations are assessed in the clinic.
a cogent case for a new approach to be applied to the development of agents, which might have activity against established disease, be effective as chemopreventives, or have a dual role. Modulation of the mechanistic targets shown in figure 3 requires the presence of chemopreventive phytochemicals at concentrations in the 10–50 mol/L range (as discussed for resveratrol49). That these agents have poor systemic availability renders such concentrations difficult to achieve in the whole organism. By contrast, much of the phytochemical could be excreted mostly unchanged to generate abundant concentrations in the gastrointestinal tract, whereas this dose might be insufficient to give systemic concentrations in the mol/L range. This property might be particularly advantageous for treatment of malignant disease in the gastrointestinal tract by use of agents such as curcumin and resveratrol, which have been shown to perturb oncogenic mechanisms in the colorectum. If these agents are to be investigated in the treatment of malignant diseases such as prostate cancer, they would need to be transported via the systemic circulation to the target organ—proof-of-concept studies are needed to show that the agent reaches the target organ in amounts sufficient to elicit activity as indicated in in-vitro experiments. Green-tea polyphenols, including epigallocatechin gallate, are not effective treatments against prostate cancer when given as monotherapy,50 but this trial did not include a quantitative assessment of polyphenols in the target tissue. Thus, it might not have reached the prostate in bioactive concentrations.
Phytochemical drug development
Conclusions
When chemopreventive phytochemicals are considered for use within a defined chemotherapeutic framework, their antineoplastic effects need to be checked in suitable animal models and ultimately in pharmacokinetic and pharmacodynamic pilot studies in human beings. The long-term experience, that we have of phytochemicals as diet constituents, suggest that they do not elicit adverse effects in human beings. Nevertheless, their safety needs utmost scrutiny, because the doses at which they are to be used will probably grossly exceed those at which they are ingested with the diet. Pilot phase I studies with suitable pharmacodynamic endpoints (or surrogate endpoints) should be designed in human beings to investigate whether the phytochemical exerts much the same activity as that seen in vitro and in vivo. Such pilot studies could be done in patients with cancer or in healthy volunteers. An especially attractive pilot experimental strategy involves the presurgery model, which allows surgical removal of tissue after patients have ingested the agent under investigation. An example of this approach is the use of curcumin in patients undergoing colectomy.38 Abbruzzese and Lippman48 have argued that cancer chemoprevention and chemotherapy should converge in clinical phase-I testing. They present
Clinical experience with the EGFR tyrosine kinase inhibitors suggests that the molecular signature of a tumour determines its susceptibility towards the effects of molecular targeted drugs,51 suggesting that oncologists will eventually want to use a range of agents capable of interfering with neoplastic cell survival in diverse ways counteracting the corollary of the different bespoke molecular signatures driving the malignant diseases. In view of the evidence emerging from studies of the mechanisms of action of chemopreventive phytochemicals (figure 3), we think that some phytochemicals at safe doses can complement new molecularly targeted or traditional anticancer drugs in counteracting the survival of malignant cells. Nevertheless, these agents tend to have low bioavailability, and the mechanisms they engage could comprise elements that antagonise, rather than augment, some activities of coadministered drugs. Therefore, more work is needed, both in terms of elucidation of primary mechanisms and discovery of new molecules, to help support or refute the hypothesis that some chemopreventive phytochemicals might be valuable in the treatment of established malignant disease. http://oncology.thelancet.com Vol 6 November 2005
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The thousands of flavonoids in the plant kingdom offer huge opportunity for agent discovery. Antineoplastic activity of chemopreventive phytochemicals in human beings will probably be difficult to show, time consuming, and expensive, the latter point being especially pertinent as powerful industrial support for these agents does not, in general, exist. This does not mean that it would not be a worthwhile undertaking. The reward could be considerable. Conflict of interest We declare no conflicts of interest. Acknowledgment We thank Stefania Filippeschi and Sue Spriggs for help with the references and the UK Medical Research Council, the US National Cancer Institute Chemoprevention Branch, and the Italian Association for Cancer Research for research support and sponsorship. References 1 Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003; 3: 768–80. 2 Dorai T, Aggarwal BB. Role of chemopreventive agents in cancer therapy. Cancer Lett 2004; 215: 129–40. 3 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 4 Pal S, Choudhuri T, Chattopadhyay S, et al. Mechanisms of curcumin-induced apoptosis of Ehrlich’s ascites carcinoma cells. Biochem Biophys Res Commun 2001; 288: 658–65. 5 Delmas D, Rebe C, Lacour S, et al. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J Biol Chem 2003; 278: 41482–90. 6 Collett GP, Campbell FC. Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 2004; 25: 2183–89. 7 Jaiswal AS, Marlow BP, Gupta N, Narayan S. -catenin-mediated transactivation and cell—cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002; 21: 8414–27. 8 Chen A, Xu J. Activation of PPAR- by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol Gastrointest Liver Physiol 2005; 288: G447–56. 9 Park MJ, Kim EH, Park IC, et al. Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial (ECV304) cells by up-regulating cyclin-dependent kinase inhibitors, p21(WAF1/CIP1), p27(KIP1) and p53. Int J Oncol 2002; 21: 379–83. 10 Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal antiinflammatory agents differ in their ability to suppress NF-kappa B activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 2004; 23: 9247–58. 11 Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 2000; 164: 6509–19. 12 Joe AK, Liu H, Suzui M, et al. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res 2002; 8: 893–903. 13 Ahmad N, Gupta S, Mukhtar H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factorB in cancer cells versus normal cells. Arch Biochem Biophys 2000, 376: 338–46. 14 Sarkar FH, Rahman KMW, Li YW. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J Nutr 2003; 133 (suppl): S2434–39.
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