Chemopreventive Phytochemicals Research Articles

Abstract 4114: Chemopreventive and chemotherapeutic effect of Withaferin-A on in vivo models of prostate cancer

Abstract Several groups have emphasized on the functional role of phytochemicals in chemoprevention and chemotherapy of prostate cancer (CaP). In this study we have focused on Withaferin A (WA) a bioactive compound derived from Withania somnifera, which has been extensively used in Asian and African traditional medicine system. In our in vitro studies, WA inhibits the growth of CRPC cells by targeting AKT mediated pro-survival signaling and simultaneously activating FOXO3a dependent apoptosis in CaP cell lines. The objective of the present study was to evaluate the in vivo efficacy of WA on both xenograft and transgenic adenocarcinoma of mouse prostrate (TRAMP) models. DU-145 and C4-2B CaP cells stably overexpressing AKT were xenografted in nude mice and WA (5mg/kg body weight) was orally administered along with control groups fed with oil alone for 4-5 weeks. AKT-overexpressing tumors showed 2-3-fold faster growth than pCMV-expressing tumors and oral administration of WA significantly reduced AKT-induced tumor growth. Immunohistochemistry of tumor sections revealed high expression of AKT, pAKT and down regulation of nuclear FOXO3a in tumor sections derived from AKT-overexpressing tumors. On the contrary, WA treated controls as well as AKT over expressed tumor sections clearly revealed that WA reverted FOXO3a mediated apoptotic signaling by down regulating AKT activation. In addition, activation of AKT has emerged as a central feature of epithelial-mesenchymal transition (EMT). Our results also revealed elevated expression of important EMT related transcription factors and genes such as snail, slug, β-catenin, vimentin, and MMPs and decrease in the expression of E-cadherin expression in AKT overexpressing tumors. Simultaneously, WA treatment of pCMV and AKT-overexpressing tumors showed decrease in the expression of these EMT markers and increase in the expression of E-cadherin. Similarly, TRAMP mice were randomized into controls and WA (oral gavage-3mg/kg body weight) for 31 weeks. Control and WA-treated mice were sacrificed periodically at 11, 20, 27 and 31 weeks. Histopathological examination revealed both the groups (control and WA-treated) showed prostatic hyperplasia with no signs of metastasis up to 20 weeks. However, 58.3% mice in the control group showed metastasis to lungs, liver or kidneys, whereas in the treatment group 16.6% mice showed metastasis in 31 weeks. Molecular analysis showed higher expression of phosphorylated AKT, FOXO3a, along with EMT markers like β-catenin, snail, vimentin and down regulation of E-cadherin expression in control-TRAMP tumors. On the other hand, WA-treated tumor tissues revealed low expression of pAKT and pFOXO3a in WA treated mice. Also, low expression of β-catenin; snail, vimentin and upregulation of E-cadherin in WA treated mice was observed. These results potentiate the chemopreventive and chemotherapeutic effects of WA in CaP and steers the clinical translation of this biomolecule. Citation Format: Suman Suman, Trinath P. Das, Murali K. Ankem, Chendil Damodaran. Chemopreventive and chemotherapeutic effect of Withaferin-A on in vivo models of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4114. doi:10.1158/1538-7445.AM2015-4114

Short-form RON overexpression augments benzyl isothiocyanate-induced apoptosis in human breast cancer cells.

Chemoprevention of breast cancer is feasible with the use of non-toxic phytochemicals from edible and medicinal plants. Benzyl isothiocyanate (BITC) is one such plant compound that prevents mammary cancer development in a transgenic mouse model in association with tumor cell apoptosis. Prior studies from our laboratory have demonstrated a role for reactive oxygen species (ROS)-dependent Bax activation through the intermediary of c-Jun N-terminal kinases in BITC-induced apoptosis in human breast cancer cells. The present study demonstrates that truncated Recepteur d'Origine Nantais (sfRON) is a novel regulator of BITC-induced apoptosis in breast cancer cells. Overexpression of sfRON in MCF-7 and MDA-MB-361 cells resulted in augmentation of BITC-induced apoptosis when the apoptotic fraction was normalized against vehicle control for each cell type (untransfected and sfRON overexpressing cells). ROS generation and G2 /M phase cell cycle arrest resulting from BITC treatment were significantly attenuated in sfRON overexpressing cells after normalization with vehicle control for each cell type. Increased BITC-induced apoptosis by sfRON overexpression was independent of c-Jun N-terminal kinase or p38 mitogen-activated protein kinase hyperphosphorylation. On the other hand, activation of Bax and Bak following BITC exposure was markedly more pronounced in sfRON overexpressing cells than in controls. sfRON overexpression also augmented apoptosis induction by structurally diverse cancer chemopreventive phytochemicals including withaferin A, phenethyl isothiocyanate, and D,L-sulforaphane. In conclusion, the present study provides novel mechanistic insights into the role of sfRON in apoptosis regulation by BITC and other electrophilic phytochemicals.

Benzo(a)pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention.

Lung cancer is the major cause of overall cancer deaths, and chemoprevention is a promising strategy to control this disease. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is one among the principal constituents of tobacco smoke that plays a key role in lung carcinogenesis. The B(a)P induced lung cancer in mice offers a relevant model to study the effect of natural products and has been widely used by many researchers and found considerable success in ameliorating the pathophysiological changes of lung cancer. Currently available synthetic drugs that constitute the pharmacological armamentarium are themselves effective in managing the condition but not without setbacks. These hunches have accelerated the requisite for natural products, which may be used as dietary supplement to prevent the progress of lung cancer. Besides, these agents also supplement the conventional treatment and offer better management of the condition with less side effects. In the context of soaring interest toward dietary phytochemicals as newer pharmacological interventions for lung cancer, in the present review, we are attempting to give a silhouette of mechanisms of B(a)P induced lung carcinogenesis and the role of dietary phytochemicals in chemoprevention.

MicroRNAs: New players in cancer prevention targeting Nrf2, oxidative stress and inflammatory pathways.

miRNAs are endogenous small non-coding RNAs of 20-22 nucleotides that repress gene expression at the post-transcriptional level. There is growing interest in the role of miRNAs in cancer chemoprevention, and several naturally occurring chemopreventive agents have been found to be modulators of miRNA expression both in vitro and in vivo. Moreover, these chemopreventive phytochemicals commonly possess anti-oxidative and/or anti-inflammatory properties, and Nrf2 has been extensively studied as a molecular target in cancer prevention. The crosstalk between miRNAs and the traditional cellular signaling pathways of chemoprevention remain to be fully elucidated. This review summarizes the data regarding the potential interactions between miRNAs and anti-oxidative and anti-inflammatory pathways. Cellular redox homeostasis can affect the biogenesis and processing of miRNAs, which in turn regulate the Nrf2 pathway of detoxifying/anti-oxidative genes. We also discuss the miRNA regulatory mechanisms in relation to inflammation-related cancer signaling pathways.

Abstract 769: Regulation of drug metabolizing enzyme and transporter gene expression by dietary and chemopreventive phytochemicals in breast cancer

Abstract Breast cancer is a leading cause of cancer-related death among American women. The etiology of majority of breast cancers is multifactorial, of which 95% is environmental and hormonal. Polycyclic aromatic hydrocarbons (PAHs) are commonly found in our environment and appear to be carcinogenic by genotoxic mechanisms. The taxanes are the most unique and successful chemotherapeutic agents used for the treatment of breast and ovarian cancer. However, multi-drug resistance (MDR) is one of the primary obstacles for successful chemotherapy. Drug metabolizing enzymes (DMEs) and transporters play important roles in modulating drug absorption, distribution, metabolism, and elimination. The regulation of gene expression of DMEs and transporters has potential impact on drug interactions of many therapeutic agents. P-glycoprotein (P-gp), Pregnane X receptor (PXR), and CYP3A are associated with MDR in breast cancer chemotherapy. Taxanes induce CYP3A by activating PXR-mediated transcription and enhance P-gp mediated drug clearance in human mammary tumor cells. Recent studies involving drug-phytochemical interactions, in addition to interactions among dietary micronutrients, indicate possibilities for improved therapeutic strategies. It is estimated that roughly 50% of cancer patients use some kind of dietary supplements. In the present study, we evaluated the ability of dietary and chemopreventive phytochemicals (curcumin and sulforaphane) on reversal of MDR induced by taxanes (paclitaxel and docetaxel). We also assessed the effects of dietary phytochemicals and taxanes, alone or in combination, on the gene expression of various DMEs, transporters, and receptors in female C57BL/6J mice exposed to the environmental PAH, 7, 12-dimethylbenz(a)anthracene (DMBA). The dietary phytochemicals suppressed the hepatic and mammary gene expression of Phase 1 (CYP1A1, 1B1) DMEs and elevated the levels of Phase 2 (NQO1) DMEs. The hepatic gene expression of CYP3A11, PXR, aryl hydrocarbon receptor and mammary gene expression of P-gp were induced in female mice exposed to DMBA and chemotherapeutic drugs (paclitaxel and docetaxel). Administration of curcumin and sulforaphane inhibited the induced gene expression levels significantly. Treatment of mice with a combination of curcumin and sulforaphane was more effective compared to treatment with either curcumin or sulforaphane alone. The differential regulation of gene expression levels reveal the potential of phytochemicals to reverse MDR in breast cancer chemotherapy. These studies will help in development of effective pharmacotherapeutic based strategies for preventing and treating human breast cancer. The studies will also lead to the development of novel combination drugs that can be used for successful chemotherapy of breast cancer in women. Citation Format: Sudha Kondraganti, Lihua Wang, Weiwu Jiang, Bhagavatula Moorthy. Regulation of drug metabolizing enzyme and transporter gene expression by dietary and chemopreventive phytochemicals in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 769. doi:10.1158/1538-7445.AM2014-769

Abstract 1266: Racial differences in the association of cruciferous vegetable intake with breast cancer hormone receptor status and tumor subtype

Abstract Background: Dietary isothiocyanates (ITCs) are chemopreventive phytochemicals from cruciferous vegetables (CV). ITCs down-regulate estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) in breast cancer cells, and inhibit development of breast cancer in animal models. CV intake was found to be inversely associated with breast cancer risk. However, the association of CV intake with breast cancer subtype is unknown. Further, racial differences exist in dietary habits and polymorphic genes in ITC-metabolizing pathway. In a prospective cohort, we examined the association of prior CV intake with breast cancer hormone receptor status and subtype by race. Methods: Among 2908 breast cancer patients diagnosed 2005-2013 at Kaiser Permanente Northern California (KPNC), data on CV intake in the past 6 months were obtained from a validated food frequency questionnaire as part of a comprehensive baseline interview about two months post-diagnosis. Breast cancer characteristics came from the KPNC Cancer Registry. CV intake and its association with hormone receptor status (ER+/-, PR+/-, and HER2+/-) and subtype (luminal A/luminal B/triple negative/HER2-overexpressing) were examined among Whites, African Americans (AA), Asians, and Hispanics. Logistic regression was used adjusting for age at diagnosis, race, menopausal status, parity, energy intake, and dietary fiber from vegetables. Results: CV intake (grams/day) differed across racial groups (p<0.01), with 46.9, 35.6, 30.7, and 27.8 for Asians, AA, Whites, and Hispanics, respectively. Except for broccoli, intake of other individual CVs differed across racial groups (p<0.01). Total CV intake was not associated with breast cancer subtypes in any racial group. However, compared with PR+ disease, coleslaw intake was associated with reduced odds of PR- disease in Asians (high vs. low: OR=0.63, 95%CI=0.41-0.97), while intake of greens including collard, kale, turnip and mustard was associated with increased odds of PR- disease in Whites (high vs. low: OR=1.34, 95%CI=1.09-1.66). Broccoli and cabbage intake were associated with reduced odds of HER2+ disease in Asians, compared with HER2- disease (high vs. low: OR=0.46, 95%CI=0.23-0.94 for broccoli, and OR=0.48, 95%CI=0.24-0.95 for cabbage). No associations were observed for Hispanics and AAs. In all racial groups combined, total CV intake, specifically broccoli intake, was associated with increased odds of luminal B, compared with luminal A subtype (OR=1.83, 95%CI= 1.19- 2.79). However, the association became null with increasing broccoli intake. Discussion: The association of CV intake with breast cancer characteristics varied by race and by individual CV. The differences may be attributable to diverse genetic background among racial groups, and specific ITCs in individual CVs. Funded by K07 CA148888 and R01 CA105274 Citation Format: Li Tang, Marilyn L. Kwan, Song Yao, Janise M. Roh, Cecile A. Laurent, Dawn L. Hershman, Schicha Kumar, Gregory E. Wilding, Christine B. Ambrosone, Lawrence H. Kushi. Racial differences in the association of cruciferous vegetable intake with breast cancer hormone receptor status and tumor subtype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2014-1266

Abstract 3255: Single oral dose pharmacokinetics of cancer chemopreventive phytochemicals from Angelica gigas Nakai in men and women

Abstract The ethanol extracts of the root of Korean herb Angelica gigas Nakai (AGN) have promising anti-cancer, anti-nociceptive and other activities in rodent models. It is currently believed that the pyranocoumarin decursin and its structural isomer decursinol angelate (DA) in such extracts contribute to the in vitro anti-cancer activity. We and others have demonstrated that both decursin and DA were extensively converted to decursinol (DOH) in rodents. However, our in vitro experiments using human and rodent S9 fractions suggested the hypothesis that decursin and/or DA might be metabolized differently in humans. Given the notable difference in the biological activities between decursin/DA and DOH, we conducted a single oral dose pharmacokinetic study of these phytochemicals in healthy volunteers to address a key question for human translatability of preclinical animal studies of decursin, DA or AGN extract. Knowing that chemicals other than decursin and DA in AGN had minimal effect on their absorption and metabolism in rodents, we used an AGN-based dietary supplement as the study drug in compliance with the FDA and institutional requirements. In all, 20 healthy subjects (10 men and 10 women) had completed the study in full. AGN product was very well tolerated by all subjects as evidenced by plasma biochemistry, complete blood cell count and physical examination. Analyzing plasma samples using UHPLC-MS/MS showed that, though humans metabolized DA slightly slower than rodents, both decursin and DA were extensively converted to DOH. Gender and racial/ethnicity do not appear to dramatically affect the PK parameters. Since we show here that humans metabolize decursin and DA in similar pattern with rodents, the anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarker data generated in rodent models will likely be relevant for human translation. In spite of the limited number of healthy individuals in the trial, this project demonstrated feasibility for our team to consider translational research in disease-oriented populations. Citation Format: Jinhui Zhang, Li Li, Thomas W. Hale, Wayne Chee, Chengguo Xing, Cheng Jiang, Junxuan Lü. Single oral dose pharmacokinetics of cancer chemopreventive phytochemicals from Angelica gigas Nakai in men and women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3255. doi:10.1158/1538-7445.AM2014-3255

Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention

The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy.

Effects of lutein and chlorophyll b on GSH depletion and DNA damage induced by cisplatin in vivo

Recent studies have proposed the use of low concentrations of phytochemicals and combinations of phytochemicals in chemoprevention to reduce cytotoxicity and simulate normal ingestion through diet. The purpose of the present study was to evaluate whether the DNA damage, chromosome instability, and oxidative stress induced by cisplatin (cDDP) are modulated by a combination of the natural pigments lutein (LT) and chlorophyll b (CLb). The protective effects observed for synergism between phytochemicals have not been completely investigated. The comet assay and micronucleus test were performed and the catalase activities and glutathione (GSH) concentrations were measured in the peripheral blood, bone marrow, liver, and kidney cells of mice. The comet assay and micronucleus test results revealed that the pigments LT and CLb were not genotoxic or mutagenic and that the pigments presented antigenotoxic and antimutagenic effects in the different cell types evaluated. This protective effect is likely related to antioxidant properties in peripheral blood cells through the prevention of cDDP-induced GSH depletion. Altogether our results show that the combination of LT and CLb, which are both usually present in the same foods, such as leafy green vegetables, can be used safely.

Pharmacogenetics, Pharmacogenomics and Epigenetics of Nrf2-regulated Xenobioticmetabolizing Enzymes and Transporters by Dietary Phytochemical and Cancer Chemoprevention

Cancer chemopreventive activities of various phytochemicals have been attributed to the modulation of xenobiotic disposition, which includes absorption, distribution, metabolism, and excretion. The interaction between xenobiotics and xenobiotic-metabolizing enzymes (XMEs) is bidirectional. XMEs are responsible for the biotransformation of xenobiotics such as bioactivation and detoxification. Conversely, xenobiotics affect XMEs through transcriptional regulation (induction or suppression) and post-translational interactions (inhibition or activation). Similar relationships also exist between xenobiotics and their transporters. Studies conducted over the past decade have demonstrated that the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), plays a critical role in the regulation of detoxifying enzymes and transporters through a signaling system that senses and responds to redox imbalance. The role of Nrf2 in the interaction between chemopreventive phytochemicals and detoxifying enzymes/transporters has become an important topic in cancer chemoprevention. In this review, the genetic and epigenetic factors that contribute to Nrf2-mediated regulation of detoxifying XMEs and transporters are discussed in the context of cancer chemoprevention. Phytochemicals may modulate the genome as well as epigenome, altering the regulation of XMEs and transporters, which may be critical for both cancer chemoprevention and the prevention of other oxidative stress- and inflammatory-related diseases, including cardiovascular, metabolic and neurological pathologies. The pharmacogenomic expression of XMEs and transporters, with an emphasis on both genomics and epigenetics, will also be discussed.

Emerging Applications of Metabolomics in Studying Chemopreventive Phytochemicals

Phytochemicals from diet and herbal medicines are under intensive investigation for their potential use as chemopreventive agents to block and suppress carcinogenesis. Chemical diversity of phytochemicals, together with complex metabolic interactions between phytochemicals and biological system, can overwhelm the capacity of traditional analytical platforms, and thus pose major challenges in studying chemopreventive phytochemicals. Recent progresses in metabolomics have transformed it to become a robust systems biology tool, suitable for examining both chemical and biochemical events that contribute to the cancer prevention activities of plant preparations or their bioactive components. This review aims to discuss the technical platform of metabolomics and its existing and potential applications in chemoprevention research, including identifying bioactive phytochemicals in plant extracts, monitoring phytochemical exposure in humans, elucidating biotransformation pathways of phytochemicals, and characterizing the effects of phytochemicals on endogenous metabolism and cancer metabolism.

Anti-inflammatory Phytochemicals for Chemoprevention of Colon Cancer

Every year more than a million new cancer cases and 600,000 deaths are reported world-wide. Colorectal cancer is the fourth most commonly occurring and second leading cause of cancer deaths in the United States. Significant progress has been made in understanding colorectal cancer through epidemiological, laboratory and clinical studies. Development of metastatic adenocarcinomas is a multistage process occurring over several years during which multiple genetic alterations and pathophysiological changes are associated. Colorectal cancer can be prevented if the transformation of normal colonic crypt cells to malignant can be halted or reversed. Some of the key molecules that are altered significantly and play important roles in colorectal tumor progression are associated with inflammation. Since chronic inflammation is now recognized as a potential risk factor for tumor development, targeting inflammatory pathways has proven effective in preventing formation of colonic tumors and their malignant progression in both preclinical and clinical studies. Synthetic non-steroidal anti-inflammatory drugs (NSAIDS) have been identified as potential colorectal cancer chemopreventive agents; however, most of these synthetic agents are associated with unwanted and sometimes fatal side effects. There is mounting evidence in support of the efficacy of naturally-occurring phytochemicals possessing anti-inflammatory activity. In this review we discuss key inflammatory pathways associated with colorectal cancer and promising naturally-occurring phytochemicals as anti-inflammatory agents for the prevention and treatment of colorectal cancer.

Bioactive Peptides/Chitosan Nanoparticles Enhance Cellular Antioxidant Activity of (−)-Epigallocatechin-3-gallate

(-)-Epigallocatechin-3-gallate (EGCG), one representative of the well-studied chemopreventive phytochemicals but with low bioavailability, was encapsulated in monodispersed nanoparticles that were assembled from bioactive caseinophosphopeptide (CPP) and chitosan (CS). The encapsulation efficiency of EGCG in CS-CPP nanoparticles ranged from 70.5 to 81.7%; meanwhile, the in vitro release of EGCG from CS-CPP nanoparticles was in a controllable manner. The EGCG-loaded CS-CPP nanoparticles exerted stronger activity of scavenging free radical than the free EGCG (p < 0.01) in the cellular antioxidant activity assay. Furthermore, cellular uptake of the EGCG-loaded CS-CPP nanoparticles was confirmed by the green fluorescence inside the human hepatocellular caricinoma (HepG2) cells, which was considered to play an important role in the improvement of the antioxidant activity of the nanoencapsulated EGCG. The results suggested that encapsulation of EGCG using CS-CPP nanoparticles should be a potential approach to enhance its antioxidant activity in biological systems.

Dietary Phytochemicals in Chemoprevention of Cancer: An Update

Dietary Phytochemicals in Chemoprevention of Cancer: An Update

Molecular mechanisms of chemopreventive phytochemicals against gastroenterological cancer development

Cancer is one of the leading causes of death worldwide. Commonly used cancer treatments, including chemotherapy and radiation therapy, often have side effects and a complete cure is sometimes impossible. Therefore, prevention, suppression, and/or delaying the onset of the disease are important. The onset of gastroenterological cancers is closely associated with an individual's lifestyle. Thus, changing lifestyle, specifically the consumption of fruits and vegetables, can help to protect against the development of gastroenterological cancers. In particular, naturally occurring bioactive compounds, including curcumin, resveratrol, isothiocyanates, (-)-epigallocatechin gallate and sulforaphane, are regarded as promising chemopreventive agents. Hence, regular consumption of these natural bioactive compounds found in foods can contribute to prevention, suppression, and/or delay of gastroenterological cancer development. In this review, we will summarize natural phytochemicals possessing potential antioxidant and/or anti-inflammatory and anti-carcinogenic activities, which are exerted by regulating or targeting specific molecules against gastroenterological cancers, including esophageal, gastric and colon cancers.

Redox modulation of pro-inflammatory and anti-inflammatory signaling by chemopreventive phytochemicals

Redox modulation of pro-inflammatory and anti-inflammatory signaling by chemopreventive phytochemicals

Emerging Roles for Modulation of microRNA Signatures in Cancer Chemoprevention

miRNAs are small endogenous non-coding RNAs, approximately 21-nucleotides in length, which are shown to regulate an array of cellular processes such as differentiation, cell cycle, cell proliferation, apoptosis, and angiogenesis which are important in cancer. miRNAs can function as both tumor promoters (oncomiRs) or tumor suppressors by their ability to target numerous biomolecules that are important in carcinogenesis. Aberrant expression of miRNAs is correlated with the development and progression of tumors, and the reversal of their expression has been shown to modulate the cancer phenotype suggesting the potential of miRNAs as targets for anti-cancer drugs. Several chemopreventive phytochemicals like epigallocatechin-3-gallate, curcumin, isoflavones, indole-3-carbinol, resveratrol, and isothiocyanate have been shown to modulate the expression of numerous miRNAs in cancer cells that lead to either abrogation of tumor growth or sensitization of cancer cells to chemotherapeutic agents. This review focuses on the putative role(s) of miRNAs in different aspects of tumorigenesis and at various stages of early drug discovery that makes them a promising class of drug targets for chemopreventive intervention in cancer. We summarize the current progress in the development of strategies for miRNA-based anti-cancer therapies. We also explore the modulation of miRNAs by various cancer chemopreventive agents and the role of miRNAs in drug metabolism. We will discuss the role of miRNAs in cancer stem cells and epithelial-to-mesenchymal transition; and talk about how modulation of miRNA expression relates to altered glycosylation patterns in cancer cells. In addition, we consider the role of altered miRNA expression in carcinogenesis induced by various agents including genotoxic and epigenetic carcinogens. Finally, we will end with a discussion on the potential involvement of miRNAs in the development of cancer chemoresistance. Taken together, a better understanding of the complex role(s) of miRNAs in cancer may help in designing better strategies for biomarker discovery or drug targeting of miRNAs and/or their putative protein targets.

Resveratrol and diallyl disulfide enhance curcumin-induced sarcoma cell apoptosis

Malignant tumors of mesenchimal origin such as rhabdomyosarcoma and osteosarcoma are highly aggressive pedriatic malignancies with a poor prognosis. Indeed, the initial response to chemotherapy is followed by chemoresistance. Diallyl disulfide (DADS), resveratrol (RES) and curcumin (CUR) are dietary chemopreventive phytochemicals which have been reported to have antineoplastic activity on rhabdomyosarcoma and osteosarcoma cells as single drugs. In this study we evaluated whether, as compared to the single compounds, the combination of DADS+RES, DADS+CUR and RES+CUR resulted in an enhancement of their antitumor potential on malignant rhabdoid (SJ-RH4, RD/18) or osteosarcoma (Saos-2) cell lines. Through FACS analysis and activated caspase-3 labeling we demonstrate that CUR induces apoptosis of rabdomyosarcoma and osteosarcoma cells and that this effect is potentiated when CUR is combined with RES or DADS. Further, we explored the effects of the compounds, alone or in combination, on signal transduction pathways involved in apoptosis and growth of cancer cells and show that in rhabdomyosarcoma cells the apoptotic effect of CUR, either alone or in combination, is independent of p53 activity. Our findings suggest that CUR and CUR-based combinations may have relevance for the treatment of p53-deficient cancers, which are often unaffected by conventional chemotherapies or radiotherapy.

Effect of Diallyl Sulfide on in Vitro and in Vivo Nrf2-Mediated Pulmonic Antioxidant Enzyme Expression via Activation ERK/p38 Signaling Pathway

Increasing oxidative stress is intimately involved in the pathogenesis of lung failure. Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a key element in redox homeostasis. Nrf2 regulates antioxidant-associated genes that are often the target of phytochemicals in chemoprevention. This study evaluated the effect of diallyl sulfide (DAS), which is present in garlic, on the expression of antioxidant enzymes in the rat lung and the Nrf2 modulation in MRC-5 lung cells. DAS increased the activities of glutathione S-transferase, glutathione reductase, and catalase as well as the GSH/GSSG ratio compared with the lung of untreated control rats (p < 0.05). The pulmonic superoxide dismutase, glutathione peroxidase, NAD(P)H:quinone oxidoreductase 1, and catalase mRNA levels were also significantly increased (p < 0.05) after DAS treatment. Following DAS treatment, DAS level was measured in the plasma after 7 days of oral administration, and the C(max) value was 15 ± 4.2 μM. The total amount of pulmonic Nrf2 and the nuclear translocation of Nrf2 were elevated in DAS-treated rats, clarifying the effect of DAS on the modulation of antioxidant enzymes. Furthermore, DAS could induce nuclear translocation of Nrf2 via ERK/p38 signaling pathway in lung MRC-5 cells. This study demonstrates that DAS administration can significantly induce the activity of antioxidant enzymes in rat lungs and suggests a possible use for DAS as a dietary preventive agent against oxidative stress-induced lung injury.

Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy

Ionizing radiation (IR)-induced cellular damage is implicated in carcinogenesis as well as therapy of cancer. Advances in radiation therapy have led to the decrease in dosage and localizing the effects to the tumor; however, the development of radioresistance in cancer cells and radiation toxicity to normal tissues are still the major concerns. The development of radioresistance involves several mechanisms, including the activation of mitogenic and survival signaling, induction of DNA repair, and changes in redox signaling and epigenetic regulation. The current strategy of combining radiation with standard cytotoxic chemotherapeutic agents can potentially lead to unwanted side effects due to both agents. Thus agents are needed that could improve the efficacy of radiation killing of cancer cells and prevent the damage to normal cells and tissues caused by the direct and bystander effects of radiation, without have its own systemic toxicity. Chemopreventive phytochemicals, usually non-toxic agents with both cancer preventive and therapeutic activities, could rightly fit in this approach. In this regard, naturally occurring compounds, including curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin and resveratrol, have shown considerable potential. These agents suppress the radiation-induced activation of receptor tyrosine kinases and nuclear factor-κB signaling, can modify cell survival and DNA repair efficacy, and may potentiate ceramide signaling. These radiosensitizing and counter radioresistance mechanisms of phytochemicals in cancer cells are also associated with changes in epigenetic gene regulation. Because radioresistance involves multiple mechanisms, more studies are needed to discover novel phytochemicals having multiple mechanisms of radiosensitization and to overcome radioresistance of cancer cells. Pre-clinical studies are needed to address the appropriate dosage, timing, and duration of the application of phytochemicals with radiation to justify clinical trials. Nonetheless, some phytochemicals in combination with IR may play a significant role in enhancing the therapeutic index of cancer treatment.