Mini-reviewRole of chemopreventive agents in cancer therapy
Introduction
Tumorigenesis is a multistep process that begins with cellular transformation, progresses to hyperproliferation and culminates in the acquisition of invasive potential, angiogenic properties and establishment of metastatic lesions [1]. This process can be activated by any one of the various environmental carcinogens (such as cigarette smoke, industrial emissions, gasoline vapors), inflammatory agents (such as tumor necrosis factor [TNF] and H2O2), tumor promoters (such as phorbol esters and okadaic acid). This multistep process of carcinogenesis consists of three phases: tumor initiation, promotion and progression phases. Several population based studies indicate that people in South East Asian countries have a much lower risk of acquiring colon, gastrointestinal, prostate, breast and other cancers when compared to their Western counterparts (see Table 1). It is very likely that constituents of their diet such as garlic, ginger, soy, curcumin, onion, tomatoes, cruciferous vegetables, chillies and green tea play an important role in their ability to avoid these cancers. These dietary agents are believed to suppress the transformative, hyperproliferative and inflammatory processes that initiate carcinogenesis. These inhibitory influences may ultimately suppress the final steps of carcinogenesis, namely angiogenesis and metastasis. These dietary agents have been classified as chemopreventive agents since their ability to delay the onset of the carcinogenic process has been studied extensively. Because these chemopreventive agents are derived from natural sources, they are considered pharmacologically safe. The focus of the current review, although brief, is to evaluate the untapped therapeutic potential of these chemopreventive agents in the setting of several molecular targets that are currently under investigation (Fig. 1).
Section snippets
Chemopreventive agents as inhibitors of the NF-κB activation pathway
NF-κB is a family of closely related protein dimers that bind to a common sequence motif in the DNA called the κB site [2]. The molecular identification of its p50 subunit (v-REL) as a member of the reticuloendotheliosis (REL) family of viruses provided the first evidence that NF-κB is linked to cancer. Research over the past decade has revealed that NF-κB is an inducible transcription factor for genes involved in cell survival, cell adhesion, inflammation, differentiation and growth. In most
Chemopreventive agents as inhibitors of the AP-1 activation pathway
Activated protein-1 (AP-1) is another transcription factor that regulates the expression of several genes that are involved in cell differentiation and proliferation. Functional activation of the AP-1 transcription complex is implicated in tumor promotion as well as malignant transformation. This complex consists of either homo or heterodimers of the members of the JUN and FOS family of proteins [17]. This AP-1 mediated transcription of several target genes can also be activated by a complex
Chemopreventive agents as inhibitors of cell proliferation and initiators of apoptosis
During the past 8 years, several reports were published which showed that activation of NF-κB promotes cell survival and proliferation and down regulation of NF-κB sensitizes the cells to apoptosis. How NF-κB promotes these proliferation and cell survival mechanisms has become increasingly clear. Expression of several genes including Bcl-2, Bcl-XL, cIAP, survivin, cyclin D1, TRAF1, TRAF2 have been reported to be up-regulated by NF-κB [2]. The proteins coded by these genes function primarily by
Chemopreventive agents as inhibitors of growth factor activation pathway
The potent cell proliferation signals generated by various growth factor receptors such as the epidermal growth factor (EGF)-receptor, insulin-like growth factor (IGF)-1 receptor and VEGF-receptor networks constitute the basis for receptor driven tumorigenicity in the progression of several cancers [1]. Consequences of these abnormal growth factor receptor signaling pathways include, besides increased cell proliferation, suppression of apoptotic signals, especially under anchorage independent
Chemopreventive agents as inhibitors of the JAK-STAT pathway
Even though cancer arises by several genetic or epigenetic mechanisms contributing to a number of abnormal oncogenic signaling pathways, all seem to converge on a very limited number of nuclear transcription factors that function as final effectors, starting specific gene expression patterns for a particular cancer. They are the canonical STAT (signal transducers and activators of transcription) family of proteins [21]. They can be activated by phosphorylation through JAK kinases or cytokine
Chemopreventive agents as inhibitors of multi-drug resistance
The use of chemotherapy to treat cancer invariably results in the development of broad resistance to a wide variety of drugs with different chemical structures and mechanisms of action. This form of resistance is mediated primarily by classical ATP-driven drug efflux pumps such as the P-glycoproteins and the MRP family of proteins. The multidrug resistance (MDR) related P-glycoprotein is inherently expressed at high levels in cancers derived from epithelial tissues such as kidney, prostate and
Chemopreventive agents as inhibitors of COX-2
Numerous preclinical studies point to the importance of regulation of cyclooxygenase-2 (COX-2) expression in the prevention and, most importantly, in the treatment of several malignancies. This enzyme is overexpressed in practically every pre-malignant and malignant conditions involving the colon, liver, pancreas, breast, lung, bladder, skin, stomach, head and neck and esophagus [27]. Overexpression of this enzyme is a consequence of deregulation of transcriptional and post-transcriptional
Chemopreventive agents as inhibitors of angiogenesis
Angiogenesis, the regulated formation of new blood vessels from existing ones, is the basis of several physiological processes such as embryonic development, placenta formation and wound healing. It is one of the best examples of how a tumor can take control of these processes and deregulate them to its own advantage. The normal and orderly formation of new blood vessels consists of the endothelial cell receiving the stimulatory signal and secretion of MMP and heparanase, which cause the
Chemopreventive agents as inhibitors of cell cycling
Even though there are literally hundreds of cancer type s with global changes in the gene expression, a very small number of crucial alterations are shared by perhaps all the tumors. These common alterations are related to those that disrupt the normal cell cycle control checkpoints. The retinoblastoma (Rb) and the tumor suppressor p53 proteins that are crucial for these controls are usually lost in several cancers. The central role of the G1 to S and the G2 to M transition and the
Chemopreventive agents as chemosensitizers and radiosensitizers
Recent reports point out that these safe and non-toxic cancer chempreventive phytochemicals can function as sensitizers, augmenting the effectiveness of cancer chemotherapy and radiotherapy. This sensitization is thought to occur at various levels. First, by directly competing with the ATP binding site of the MDR or MRP drug efflux pumps, curcumin can inhibit the pump and increase the intracellular concentrations of the chemotherapeutic drugs such as vinblastine or vincristine. Second, by
Conclusions
This minireview presents evidence that chemopreventive agents can be used not just to prevent cancer but also to treat cancer. Because of their pharmacological safety, most chemopreventive agents can be used in combination with chemotherapeutic agents to enhance the effect at lower doses and thus minimize chemotherapy-induced toxicity. Because cancer is primarily a disease of old age, less toxic therapy is a major priority. This review reveals that molecular targets of chemopreventive agents
Acknowledgements
This work was supported by the Clayton Foundation for Research (to BBA), Department of Defense US Army Breast Cancer Research Program Grant (BC010610, to BBA), a PO1 grant (CA91844, to BBA) from the National Institutes of Health on lung chemoprevention, and a P50 Head and Neck SPORE grant from the National Institutes of Health (to BBA).
References (55)
- et al.
Activation of transcription factor NF-kB is suppressed by curcumin (Diferuloylmethane)
J. Biol. Chem.
(1995) - et al.
Sanguinarine (pseudochelerythrine) is a potent inhibitor of NF-kB activation, IkBa phophorylation and degradation
J. Biol. Chem.
(1997) - et al.
Flavopiridol inhibits NF-kB activation induced by various carcinogens and inflammatory agents through inhibition of Ikappa Balpha kinase and p65 phosphorylation: abrogation of CyclinD1, cyclooxygenase-2 and matrix metalloproteinase-9
J. Biol. Chem.
(2004) - et al.
Nuclear factor-kappa B and cancer: its role in prevention and therapy
Biochem. Pharmacol.
(2002) - et al.
Modulation of P-Glycoprotein expression and function by curcumin in multi-drug resistant human KB cells
Biochem. Pharmacol.
(2002) - et al.
Involvement of multidrug resistance associated proteins in regulating the cellular levels of (−)-epigallocatechin-3- gallate and its methyl metabolites
Biochem. Biophys. Res. Commun.
(2003) - et al.
Cyclooxygenase-2: a molecular target for chemoprevention and treatment
Trends Pharmacol. Sci.
(2003) - et al.
Cyclooxygenase-2: a therapeutic target for angiogenesis
Trends Mol. Med.
(2003) - et al.
Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells
J. Biol. Chem.
(1998) - et al.
Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase
Fed. Eur. Biochem. Soc. Lett.
(1994)
Direct inhibitory effect of curcumin on src and focal adhesion kinase activity
Biochem. Pharmacol.
Irreversible inhibition of CD13/AminopeptidaseN by the anti-angiogenic agent curcumin
Chem. Biol.
Resveratrol blocks interleukin-1[beta]-induced activation of the nuclear transcription factor NF-[kappa]B, inhibits proliferation, causes S-phase arrest and induces apoptosis of acute myeloid leukemia cells
Blood
Curcumin(diferuloylmethane) down regulates the constitutive activation of nuclear factor kappa B and Ikappa B alpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis
Blood
Molecular pathway for (−)- epigallocatechin-3-gallate induced cell cycle arrest and apoptosis of human prostate carcinoma cells
Arch. Biochem. Biophys.
Induction of apoptosis by curcumin:mediation by glutathione S-transferase P1-1 inhibition
Biochem. Pharmacol.
Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway
J. Biol. Chem.
Rules for making human tumor cells
New. Engl. J. Med.
Nuclear transcription factor-kB as a target for cancer drug development
Leukemia
Capsaicin (8-methyl-N-vanillyl-6-noneamide) is a potent inhibitor of the transcription factor NF-kB activation by diverse agents
J. Immunol.
Caffeic acid phenethyl ester (CAPE) is a potent and specific inhibitor of activation of nuclear transcription factor NF-kB
Proc. Natl Acad. Sci. USA
Emodin (3-methyl-1,6,8-trihydroxy anthraquinone) inhibits the TNF-induced NF-kB activation, IkB degradation and expression of cell surface adhesion proteins in human vascular endothelial cells
Oncogene
Silymarin suppresses TNF induced activation of nuclear transcription factor-kB, c-Jun N-terminal kinase and apoptosis
J. Immunol.
Oleandrin suppresses the activation of nucler transcription factor-kB, activator protein-1 and c-Jun N-terminal kinase
Cancer Res.
Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kB, Activator protein-1 and apoptosis: Potential role of reactive oxygen intermediates and lipid peroxidation
J. Immunol.
Piceatannol inhibits TNF-induced NF-kB activation and NF-kB mediated gene expression through suppression of IkappaBalpha kinase and p65 phosphorylation
J. Immunol.
Ursolic acid inhibits nuclear factor-kB activation induced by carcinogenic agents through suppression of IkBα Kinase and p65 phosphorylation: correlation with down regulation of COX-2, MMP-9 and cyclinD1
Cancer Res.
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