curcumin and indole-3-carbinol

Lung cancer is a prominent cause of cancer-associated mortality worldwide. The main reason for high mortality due to lung cancer is attributable to the fact that the diagnosis is generally made when it has spread beyond a curable stage and cannot be treated surgically or with radiation therapy. Therefore, new approaches like dietary modifications could be extremely useful in reducing lung cancer incidences. Several fruits and vegetables offer a variety of bioactive compounds to afford protection against several diseases, including lung cancer. A number of research studies involving dietary agents provide strong evidence for their role in the prevention and treatment of lung cancer, and have identified their molecular mechanisms of action and potential targets. In this review article, we summarize data from in-vitro and in-vivo studies and where available, in clinical trials, on the effects of some of the most promising dietary agents against lung cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Catechin; Curcumin; Flavonoids; Flavonols; Humans; Indoles; Isothiocyanates; Lung Neoplasms; Plant Extracts; Polyphenols

Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs.

Topics: Abietanes; Alkaloids; Allyl Compounds; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; beta Carotene; Biflavonoids; Capsaicin; Catechin; Catechols; Curcumin; Dietary Supplements; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Fatty Alcohols; Furocoumarins; Humans; Indoles; Limonins; Neoplasms; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Proanthocyanidins; Quercetin; Resveratrol; Stilbenes; Sulfides; Tea; Triterpenes; Xanthophylls

Cancer cells are known to have alterations in multiple cellular signaling pathways and because of the complexities in the communication between multiple signaling networks, the treatment and the cure for most human malignancies is still an open question. Perhaps, this is the reason why specific inhibitors that target only one pathway have been typically failed in cancer treatment. However, the in vitro and in vivo studies have demonstrated that some natural products such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), resveratrol, lycopene, etc, have inhibitory effects on human and animal cancers through targeting multiple cellular signaling pathways and thus these "natural agents" could be classified as multi-targeted agents. This is also consistent with the epidemiological studies showing that the consumption of fruits, soybean and vegetables is associated with reduced risk of several types of cancers. By regulating multiple important cellular signaling pathways including NF-kappaB, Akt, MAPK, Wnt, Notch, p53, AR, ER, etc, these natural products are known to activate cell death signals and induce apoptosis in pre-cancerous or cancer cells without affecting normal cells. Therefore, non-toxic "natural agents" harvested from the bounties of nature could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

Topics: Antineoplastic Agents; Carotenoids; Catechin; Curcumin; Humans; Indoles; Isoflavones; Lycopene; Neoplasms; Resveratrol; Signal Transduction; Stilbenes

There is a large body of evidence that the consumption of fruit and vegetables can decrease the risk of cancer. However, the link between diet and health is extremely complex. Some dietary phytochemicals seem to offer protection in an exposure-related manner and many molecular targets and signaling pathways affected by phytochemicals have been discovered. Although in vitro studies have contributed significantly to our understanding, quite a number use concentrations orders of magnitude greater than those achievable in humans or toxic to normal tissues (exemplified by toxic concentrations of indole-3-carbinol, epigallocatechin-3-gallate, curcumin, and genistein for breast cells). Such studies may produce results that are physiologically irrelevant, thus hindering predictions of efficacy. Here, we argue for careful consideration to be given to the in vitro experimental conditions under which dietary phytochemicals are investigated. Design features, such as the use of appropriate nontoxic concentrations, extended treatment times, three-dimensional cultures, primary tumor cultures, and comparison of susceptibility of various cancer subtypes, should improve our understanding of their molecular targets. This in turn would facilitate predictions as to their potential usefulness in the clinic.

Topics: Animals; Catechin; Cell Transformation, Neoplastic; Curcumin; Diet; Food; Fruit; Genistein; Humans; Indoles; Mice; Models, Biological; Neoplasms; Phytotherapy; Vegetables

Cancer cells exhibit deregulation in multiple cellular signaling pathways. Therefore, treatments using specific agents that target only one pathway usually fail in cancer therapy. The combination treatments using chemotherapeutic agents with distinct molecular mechanisms are considered more promising for higher efficacy; however, using multiple agents contributes to added toxicity. Emerging evidence has shown that some "natural products" such as isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin among many others, have growth inhibitory and apoptosis inducing effects on human and animal cancer cells mediated by targeting multiple cellular signaling pathways in vitro without causing unwanted toxicity in normal cells. Therefore, these non-toxic "natural products" from natural resources could be useful in combination with conventional chemotherapeutic agents for the treatment of human malignancies with lower toxicity and higher efficacy. In fact, recently increasing evidence from pre-clinical in vivo studies and clinical trials have shown some success in support of the use of rational design of multi-targeted therapies for the treatment of cancers using conventional chemotherapeutic agents in combination with "natural products". These studies have provided promising results and further opened-up newer avenues for cancer therapy. In this review article, we have succinctly summarized the known effects of "natural products" especially by focusing on isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin, and provided a comprehensive view on the molecular mechanisms underlying the principle of cancer therapy using combination of "natural products" with conventional therapeutics.

Topics: Animals; Antineoplastic Agents; Biological Products; Curcumin; Humans; Indoles; Isoflavones; Neoplasms

There is growing interest in the ability of phytochemicals to prevent chronic diseases, such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in-depth studies into their mechanisms of action have been carried out in vitro using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole-3-carbinol, diindolylmethane, curcumin, epigallocatechin-3-gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally, the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus, for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. However, data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Catechin; Curcumin; Humans; Indoles; Neoplasms; Resveratrol; Stilbenes

As cancer chemopreventive agents are intended for use by healthy individuals as prophylactics to prevent or retard the development of cancer, they must be amenable to ingestion over prolonged periods without toxicity. Therefore, putative chemopreventive agents need to undergo stringent testing to ensure their safety with regard to chronic exposure in humans. The diet is thought to be a source of chemopreventive agents, and dietary compounds are generally considered to be of low hazard, albeit this notion has not often been put to the test. Here the safety information available for 5 dietary putative chemopreventive compounds, indole-3-carbinol (I3C), curcumin, quercetin, epigallocatechin gallate (EGCG), and capsaicin is reviewed. For these agents, normal dietary intake, doses used in clinical trials, efficacious doses in rodents, and where available, toxic doses are compared. For curcumin, quercetin and capsaicin, toxicological data is only available from studies in rodents. Information on long-term effects in animals beyond 28 or 90 days is lacking for EGCG. Capsaicin and quercetin are suspected carcinogens. I3C and quercetin can modulate the absorption of other drugs given concomitantly. Without further investigation of their toxicology, it is difficult to recommend any of these agents for long-term use in the healthy population.

Topics: Antineoplastic Agents, Phytogenic; Capsaicin; Catechin; Chemoprevention; Consumer Product Safety; Curcumin; Diet; Humans; Indoles; Male; Neoplasms; Quercetin; Toxicity Tests

Many dietary constituents are chemopreventive in animal models, and experiments with cultured cells are revealing various potential mechanisms of action. Compounds classified as blocking agents can prevent, or greatly reduce, initiation of carcinogenesis, while suppressing agents affect later stages of the process by reducing cell proliferation. Many compounds have both types of activity. Blocking mechanisms include alteration of drug metabolising activities and scavenging of reactive oxygen species. Mechanisms which suppress tumorigenesis often involve modulation of signal transduction pathways, leading to altered gene expression, cell cycle arrest or apoptosis. As our knowledge of how these dietary components affect cell biochemistry improves, so the likelihood of success in chemoprevention trials and in provision of dietary advice to the general population to optimise the chances of preventing disease is increased.

Topics: Anticarcinogenic Agents; Apoptosis; Arachidonic Acid; Cell Cycle; Curcumin; Diet; Enzyme Inhibitors; Free Radical Scavengers; Humans; Indoles; Neoplasms; Signal Transduction

Cancer cells meet their energy need by predominantly increased uptake of glucose, high rate of glycolysis, and increased production of lactate even in the presence of adequate oxygen.  This process was proposed by Otto Warburg and named after him as the Warburg effect. The development of drugs that target glucose intake and aerobic glycolysis or lactic acid secretion of cancer cells is a newer approach for drug discovery. We have tested five purified plants-derived compounds such as curcumin, quercetin, ellagic acid, resveratrol, and indole-3-carbinol in HeLa cells for cytotoxicity, inhibition of metastasis, and modulation of lactate-pyruvate metabolism. Standard biochemical methods were used for glucose, lactic acid, and pyruvic acid measurement. The cell viability was determined by MTT assay. Cell migration was checked by wound healing assay. A dose-dependent cytotoxic effect and inhibition of cell migration were observed in all the tested compounds. A decrease in the lactate and increase in pyruvate level was observed in all the tested compounds except ellagic acid. Our finding suggests that tested phytocompounds are associated with the metabolic reprogramming of cancer cells and execute the cytotoxic effect. These compounds could be used for cancer prevention and therapy.

Topics: Antineoplastic Agents, Phytogenic; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Indoles; Lactic Acid; Pyruvic Acid; Quercetin; Resveratrol; Tumor Cells, Cultured

Hepatic stellate cells (HSC) play a pivotal role in liver fibrosis, and the clearance of activated HSC by apoptosis is associated with the resolution of liver fibrosis. The development of strategies that promote this process in a selective way is therefore important. We evaluated the effects of indole-3-carbinol (I3C), a nutritional component derived from vegetables from the Brassica family, on liver fibrosis and HSC apoptosis. The in vivo therapeutic effects of I3C were monitored in three rat models of liver fibrosis induced by porcine serum, bile duct ligation, or multiple hepatotoxic factors, and its proapoptotic effect and molecular mechanism were studied in vitro in HSC-T6, a rat HSC line. The results showed that I3C treatment significantly reduced the number of activated HSC in the livers of rats with liver fibrosis. In histopathology, I3C reduced hepatocyte degeneration and necrosis, accelerated collagen degradation, and promoted the reversal of liver fibrosis. I3C prescribed to HSC-T6 resulted in morphologic alterations typical of apoptosis and DNA cleavage to a nucleosomal ladder. Moreover, I3C significantly increased the HSC-T6 apoptosis rate and the expression ratio of Bax to Bcl-2. High-throughput protein array analysis indicated that the tumor necrosis factor-α/nuclear factor-κB (NF-κB) signal pathway participated in I3C-induced HSC-T6 apoptosis. Western blot and electrophoretic mobility-shift assay confirmed that I3C inhibited the phosphorylation of inhibitor of κB kinase α and inhibitor of κB-α and NF-κB DNA binding activity. In conclusion, I3C could promote the reverse process of liver fibrosis in vivo and induce apoptosis of activated HSC in vitro, which indicates the use of I3C as a potential therapeutic agent in liver fibrosis treatment.

Topics: Animals; Apoptosis; Bile Ducts; Carbon Tetrachloride; Curcumin; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Hepatic Stellate Cells; I-kappa B Kinase; I-kappa B Proteins; Indoles; Liver; Liver Cirrhosis; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Protein Array Analysis; Rats; Rats, Wistar; Signal Transduction; Solvents; Swine; Transfection

This study is to investigate the therapeutic effect and mechanism of indole-3-carbinol (I3C) on pig serum-induced liver fibrosis of rats. The liver fibrotic model of rats was induced by pig serum. After models were successfully established, rats in the treatment groups were administered with I3C through intraperitoneal injection or curcumin by intragastric administration, daily for 17 days. Hepatic hydroxyproline (Hyp) content was measured. The liver histology and immunohistochemistry with a-smooth muscle actin (alpha-SMA) were assayed. Hepatic stellate cells line, HSC-T6 was incubated with different concentrations of I3C (25, 50, and 100 micromol x L(-1)) for 24 h. The effect of I3C on cell apoptosis was identified by FITC-Annexin V/PI double labeled assay. And the mRNA expressions of Bax and Bcl-2 were measured by real time RT-PCR. The results showed that hepatic content of Hyp decreased by I3C treatment, as compared with the fibrotic model control. Histopathological changes, such as steatosis, necrosis, deposition of collagenous fiber reduced remarkably and the expression of alpha-SMA was significantly down-regulated in the I3C-treated groups (P < 0.01). Apoptosis analysis showed that I3C significantly increased HSC-T6 apoptosis rate and the expressional ratio of Bax to Bcl-2. The results indicated that I3C could effectively cure pig serum-induced liver fibrosis in vivo by inducing HSC apoptosis and promoting ECM degradation.

Topics: Actins; Animals; Apoptosis; bcl-2-Associated X Protein; Cell Line; Collagen; Curcumin; Enzyme Inhibitors; Hepatic Stellate Cells; Hydroxyproline; Indoles; Liver; Liver Cirrhosis, Experimental; Male; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; RNA, Messenger; Serum; Swine

Dietary phytochemicals exhibit chemopreventive potential in vivo through persistent low-dose exposures, whereas mechanistic in vitro studies with these agents generally use a high-dose single treatment. Because the latter approach is not representative of an in vivo steady state, we investigated antitumor activity of curcumin, 3,3'-diindolylmethane (DIM), epigallocatechin gallate (EGCG), genistein, or indole-3-carbinol (I3C) in breast cancer MDA-MB-231 cells, exposed in long-term culture to low concentrations, achievable in vivo. Curcumin and EGCG increased cell doubling time. Curcumin, EGCG, and I3C inhibited clonogenic growth by 55% to 60% and induced 1.5- to 2-fold higher levels of the basal caspase-3/7 activity. No changes in expression of cell cycle-related proteins or survivin were found; however, I3C reduced epidermal growth factor receptor expression, contributing to apoptosis. Because some phytochemicals are shown to inhibit DNA and histone modification, modulation of expression by the agents in a set of genes (cadherin-11, p21Cip1, urokinase-type plasminogen activator, and interleukin-6) was compared with changes induced by inhibitors of DNA methylation or histone deacetylation. The phytochemicals modified protein and/or RNA expression of these genes, with EGCG eliciting the least and DIM the most changes in gene expression. DIM and curcumin decreased cadherin-11 and increased urokinase-type plasminogen activator levels correlated with increased cell motility. Curcumin, DIM, EGCG, and genistein reduced cell sensitivity to radiation-induced DNA damage without affecting DNA repair. This model has revealed that apoptosis and not arrest is likely to be responsible for growth inhibition. It also implicated new molecular targets and activities of the agents under conditions relevant to human exposure.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Catechin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Diet; DNA Damage; Gene Expression Regulation, Neoplastic; Genistein; Humans; Indoles; Neoplasm Proteins; Neoplasms; RNA, Neoplasm; Time Factors

Epidemiological studies have long hinted at the possibility that what we eat greatly influences our state of health, in particular our relative risk of developing cancer. In recent years there has been an exponential increase in the number of studies investigating how individual components of the diet interact at the molecular level to determine the fate of a cell. It is now apparent that many such molecules can preferentially inhibit the growth of tumour cells, by inducing cell cycle arrest or apoptosis. The number of signalling pathways and molecular targets involved is continually expanding. Consequently, the picture is becoming ever more complicated, not least because results often appear to be cell-type specific, dose-response relationships are critical, and any one agent appears to have multiple mechanisms of action. In addition most studies have been conducted in cell culture, often with physiologically unachievable concentrations of single agents, making extrapolation to the clinical situation difficult. In this review the mechanisms of action of a few well-studied dietary polyphenols (curcumin, epigallocatechin gallate and resveratrol) and indole-3 carbinol are considered in the light of these issues.

Topics: Apoptosis; Catechin; Cell Cycle; Curcumin; Flavonoids; Humans; Indoles; Mitogen-Activated Protein Kinases; Neoplasms; NF-kappaB-Inducing Kinase; Phenols; Polyphenols; Protein Serine-Threonine Kinases; Signal Transduction; STAT Transcription Factors

We assessed the ability of some natural products--namely, curcumin, resveratrol, indole-3-carbinol, and ellagic acid--to modify the DNA damaging ability of the alkylating carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in cultured Chinese hamster lung fibroblast cells (CH V-79). MNNG produced DNA single strand breaks in a dose- and time-dependent manner, as observed by increase in the tail moments of the comet, when the cells were subjected to alkaline single cell gel electrophoresis. When the cells were treated in the presence of each of the natural compounds, the DNA damage caused by MNNG was considerably reduced. This effect was found to be dose related. Preincubation of cells with each of these compounds individually afforded significant protection to DNA against damage caused by subsequent treatment with MNNG, indicating a true chemopreventive role of these substances. The most remarkable aspect of the present study was that all four compounds helped in the recovery of DNA damage by accelerating DNA repair efficiency in the damaged cells. This was further substantiated by the observation on unscheduled DNA synthesis. Our results suggest that these agents are chemopreventive by virtue of their ability to protect DNA as well as to induce DNA repair.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinogens; Cell Culture Techniques; Comet Assay; Cricetinae; Cricetulus; Curcumin; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Ellagic Acid; Fibroblasts; Indoles; Methylnitronitrosoguanidine; Resveratrol; Stilbenes

The human diet contains a variety of compounds that exhibit chemopreventive effects towards an array of xenobiotics. In the present study, the antigenotoxic potential of selected dietary constituents including Diallyl sulfide (DAS), Indole-3-carbinol (I3C), Curcumin (CUR), and Black tea polyphenols (BTP) has been evaluated in the Salmonella typhimurium reverse mutation and mammalian in vivo cytogenetic assays. In addition, the anticlastogenic effect of the above dietary constituents was identified towards Benzo(a)pyrene (BaP) and cyclophosphamide- (CP) induced cytogenetic damage in mouse bone marrow cells. The induction of BaP and CP induced chromosomal aberrations, micronuclei formation, and sister chromatid exchanges (SCEs) were found to be inhibited in a dose-dependent manner by DAS, I3C, CUR, and BTP. Thus the study reveals the antimutagenic potential of these dietary compounds towards BaP- and CP-induced genotoxicity in microbial and mammalian test systems.

Topics: Allyl Compounds; Animals; Antimutagenic Agents; Benzo(a)pyrene; Bone Marrow Cells; Chromosome Aberrations; Curcumin; Cyclophosphamide; Diet; Dose-Response Relationship, Drug; Flavonoids; Indoles; Male; Mice; Micronuclei, Chromosome-Defective; Mutagenicity Tests; Phenols; Polymers; Salmonella typhimurium; Sister Chromatid Exchange; Sulfides; Tea