Omer Kucuk

Perspectives for Cancer Prevention With Natural Compounds

Cancer is the second leading cause of death in the United States. Despite the estimated 565,650 deaths in 2008 of Americans as a result of cancer, it is mostly a preventable disease. Simply by modification of diet, maintenance of optimum body weight, and regular physical activity, 30% to 40% of all instances of cancer could be prevented. Modification of diet alone by increasing vegetable and fruit intake could prevent 20% or more of all cases of cancer and may potentially prevent approximately 200,000 cancer-related deaths annually. Because of their safety, low toxicity, antioxidant properties, and general acceptance as dietary supplements, fruits, vegetables, and other dietary elements (phytochemicals and minerals) are being investigated for the prevention of cancer. Extensive research over the past several decades has identified numerous dietary and botanical natural compounds that have chemopreventive potential. In this review, we discuss promising natural chemopreventive compounds, their molecular targets, and their mechanisms, which may help the further design and conduct of preclinical and clinical trials.

Cancer Prevention With Natural Compounds

Botanical and nutritional compounds have been used for the treatment of cancer throughout history. These compounds also may be useful in the prevention of cancer. Population studies suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great interest. There are numerous reports of cancer chemopreventive activity of dietary botanicals, including cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and onion, green tea, Citrus fruits, soybeans, tomatoes, berries, and ginger, as well as medicinal plants. Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action.

Sensitization of Cervical Cancer Cells to Cisplatin by Genistein: The Role of NFκB and Akt/mTOR Signaling Pathways

Cervical cancer is among the top causes of death from cancer in women. Cisplatin-based chemotherapy has been shown to improve survival; however, cisplatin treatment is associated with toxicity to healthy cells. Genistein has been used as an adjunct to chemotherapy to enhance the activity of chemotherapeutic agents without causing increased toxicity. The present study was designed to investigate the effect of genistein (25 μM) on antitumor activity of cisplatin (250 nM) on HeLa cervical cancer cells. We have examined the alterations in expression of NF-κB, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt protein levels in response to treatment. The combination of 25 μM genistein with 250 nM cisplatin resulted in significantly greater growth inhibition (P < 0.01). Genistein enhanced the antitumor activity of cisplatin and reduced the expression of NF-κB, p-mTOR, p-p70S6K1, p-4E-BP1, and p-Akt. The results in the present study suggest that genistein could enhance the activity of cisplatin via inhibition of NF-κB and Akt/mTOR pathways. Genistein is a promising nontoxic nutritional agent that may enhance treatment outcome in cervical cancer patients when given concomitantly with cisplatin. Clinical trials of genistein and cisplatin combination are warranted to test this hypothesis.

Soy Isoflavones in Conjunction With Radiation Therapy in Patients With Prostate Cancer

Soy isoflavones sensitize prostate cancer cells to radiation therapy by inhibiting cell survival pathways activated by radiation. At the same time, soy isoflavones have significant antioxidant and anti-inflammatory activity, which may help prevent the side effects of radiation. Therefore, we hypothesized that soy isoflavones could be useful when given in conjunction with curative radiation therapy in patients with localized prostate cancer. In addition to enhancing the efficacy of radiation therapy, soy isoflavones could prevent the adverse effects of radiation. We conducted a pilot study to investigate the effects of soy isoflavone supplementation on acute and subacute toxicity (≤6 mo) of external beam radiation therapy in patients with localized prostate cancer. Forty-two patients with prostate cancer were randomly assigned to receive 200 mg soy isoflavone (Group 1) or placebo (Group 2) daily for 6 mo beginning with the first day of radiation therapy, which was administered in 1.8 to 2.5 Gy fractions for a total of 73.8 to 77.5 Gy. Adverse effects of radiation therapy on bladder, bowel, and sexual function were assessed by a self-administered quality of life questionnaire at 3 and 6 mo. Only 26 and 27 patients returned completed questionnaires at 3 and 6 mo, respectively. At each time point, urinary, bowel, and sexual adverse symptoms induced by radiation therapy were decreased in the soy isoflavone group compared to placebo group. At 3 mo, soy-treated patients had less urinary incontinence, less urgency, and better erectile function as compared to the placebo group. At 6 mo, the symptoms in soy-treated patients were further improved as compared to the placebo group. These patients had less dripping/leakage of urine (7.7% in Group 1 vs. 28.4% in Group 2), less rectal cramping/diarrhea (7.7% vs. 21.4%), and less pain with bowel movements (0% vs. 14.8%) than placebo-treated patients. There was also a higher overall ability to have erections (77% vs. 57.1%). The results suggest that soy isoflavones taken in conjunction with radiation therapy could reduce the urinary, intestinal, and sexual adverse effects in patients with prostate cancer.

EPLIN downregulation promotes epithelial–mesenchymal transition in prostate cancer cells and correlates with clinical lymph node metastasis

Epithelial–mesenchymal transition (EMT) is a crucial mechanism for the acquisition of migratory and invasive capabilities by epithelial cancer cells. By conducting quantitative proteomics in experimental models of human prostate cancer (PCa) metastasis, we observed strikingly decreased expression of EPLIN (epithelial protein lost in neoplasm; or LIM domain and actin binding 1, LIMA-1) upon EMT. Biochemical and functional analyses demonstrated that EPLIN is a negative regulator of EMT and invasiveness in PCa cells. EPLIN depletion resulted in the disassembly of adherens junctions, structurally distinct actin remodeling and activation of β-catenin signaling. Microarray expression analysis identified a subset of putative EPLIN target genes associated with EMT, invasion and metastasis. By immunohistochemistry, EPLIN downregulation was also demonstrated in lymph node metastases of human solid tumors including PCa, breast cancer, colorectal cancer and squamous cell carcinoma of the head and neck. This study reveals a novel molecular mechanism for converting cancer cells into a highly invasive and malignant form, and has important implications in prognosis and treating metastasis at early stages.

Genistein cooperates with the histone deacetylase inhibitor vorinostat to induce cell death in prostate cancer cells

BackgroundAmong American men, prostate cancer is the most common, non-cutaneous malignancy that accounted for an estimated 241,000 new cases and 34,000 deaths in 2011. Previous studies have suggested that Wnt pathway inhibitory genes are silenced by CpG hypermethylation, and other studies have suggested that genistein can demethylate hypermethylated DNA. Genistein is a soy isoflavone with diverse effects on cellular proliferation, survival, and gene expression that suggest it could be a potential therapeutic agent for prostate cancer. We undertook the present study to investigate the effects of genistein on the epigenome of prostate cancer cells and to discover novel combination approaches of other compounds with genistein that might be of translational utility. Here, we have investigated the effects of genistein on several prostate cancer cell lines, including the ARCaP-E/ARCaP-M model of the epithelial to mesenchymal transition (EMT), to analyze effects on their epigenetic state. In addition, we investigated the effects of combined treatment of genistein with the histone deacetylase inhibitor vorinostat on survival in prostate cancer cells.MethodsUsing whole genome expression profiling and whole genome methylation profiling, we have determined the genome-wide differences in genetic and epigenetic responses to genistein in prostate cancer cells before and after undergoing the EMT. Also, cells were treated with genistein, vorinostat, and combination treatment, where cell death and cell proliferation was determined.ResultsContrary to earlier reports, genistein did not have an effect on CpG methylation at 20 μM, but it did affect histone H3K9 acetylation and induced increased expression of histone acetyltransferase 1 (HAT1). In addition, genistein also had differential effects on survival and cooperated with the histone deacteylase inhibitor vorinostat to induce cell death and inhibit proliferation.ConclusionOur results suggest that there are a number of pathways that are affected with genistein and vorinostat treatment such as Wnt, TNF, G2/M DNA damage checkpoint, and androgen signaling pathways. In addition, genistein cooperates with vorinostat to induce cell death in prostate cancer cell lines with a greater effect on early stage prostate cancer.

Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy

Objectives. To determine the relationship between preoperative erythrocyte sedimentation rate (ESR) and overall survival in localized renal cell carcinoma (RCC) following nephrectomy. Methods. 167 patients undergoing nephrectomy for localized RCC had ESR levels measured preoperatively. Receiver Operating Characteristics curves were used to determine Area Under the Curve and relative sensitivity and specificity of preoperative ESR in predicting overall survival. Cut-offs for low (0.0–20.0 mm/hr), intermediate (20.1–50.0 mm/hr), and high risk (>50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based groups on overall survival. Univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics. Results. Overall, 55.2% were low risk, while 27.0% and 17.8% were intermediate and high risk, respectively. Median (95% CI) survival was 44.1 (42.6–45.5) months, 35.5 (32.3–38.8) months, and 32.1 (25.5–38.6) months, respectively. After controlling for other patient and tumor characteristics, intermediate and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735–27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117–162.228) increased risk of overall mortality, respectively. Conclusion. Preoperative ESR values represent a robust predictor of overall survival following nephrectomy in localized RCC.

PDGF Upregulates Mcl-1 Through Activation of β-Catenin and HIF-1α-Dependent Signaling in Human Prostate Cancer Cells

Background Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. Methodology/Principal Findings Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. Conclusions/Significance Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis.

Carotenoids and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem around the world, especially in developed countries. NAFLD includes all cases of fatty liver disease from simple steatosis to cirrhosis, without excessive alcohol intake, use of steatogenic medication or hereditary disorders. Pathogenesis is associated with dietary high fat intake, decreased free fatty acid (FFA) oxidation, increased hepatic lipogenesis and lipolysis from the adipose tissue. These metabolic alterations contribute to the hepatic fat accumulation. Consequently, stimulated oxidative stress and inflammation play a major role in hepatocellular damage. Therefore, antioxidant and anti-inflammatory agents may have a role in the prevention of this disease. Carotenoids are potent antioxidant and anti-inflammatory micronutrients, which have been investigated in the prevention and treatment of NAFLD. The main sources of the carotenoids are fruits and vegetables. In this article we review the potential role and possible molecular mechanism of carotenoids in NAFLD.

Dietary Agents in Cancer Chemoprevention and Treatment

Cancer chemoprevention using natural or synthetic compounds to prevent or suppress the development of cancer, is an area of active investigation. Many compounds belonging to diverse chemical classes have been identified as potential chemopreventive agents, including vitamins and minerals, naturally occurring phytochemicals, and synthetic compounds. Understanding the molecular mechanisms of cancer chemoprevention is not only important for the safe application of these compounds in populations of patients at high risk for cancer, but also allows for further development of novel treatment regimens for cancer patients. This special issue contains original research as well as review articles that are intended to stimulate the continuing efforts to understand the use of dietary agents in cancer chemoprevention and treatment. The lead article by S. N. Saldanha and T. O. Tollefsbol provides a comprehensive review of dietary agents that have shown strong chemopreventive and therapeutic properties in vitro. They also discuss the design and modification of these bioactive compounds for pre-clinical and clinical applications. Dietary intake of foods rich in antioxidant compounds has been suggested to be cancer protective. However, randomized clinical trials and epidemiologic studies on the association between intake of foods rich in antioxidants and cancer incidence have yielded mixed results. M. Y. Wei and E. L. Giovannuci discuss the epidemiologic considerations of lycopene as a chemopreventive agent, including measurement of lycopene, its major source in the diet, and the assessment of prostate cancer incidence and progression, with particular emphasis on the effect of PSA screening on this association. K. Zhou and J. J. Raffoul discuss the composition and cancer-protective effects of major phenolic antioxidants in grape skin and grape seed extracts. M. A. Parasramka and S. V. Gupta provide original research demonstrating the anticancer properties of garcinol alone, or combined with curcumin, on pancreatic cancer cells. Garcinol, a polyisoprentylated benzophenone extracted from the rind of the fruit Garcinia indica, a plant found in tropical regions, has antioxidant and anti-inflammatory properties and its role as anticancer agent is thoroughly discussed in the review from N. Saadat and S. V. Gupta. Two manuscripts discussing the effect of dietary agents on DNA repair capacity are also part of this special issue. In a manuscript by J. J. Raffoul et al., the potential for targeting the DNA base excision repair enzyme APE1/Ref-1 using dietary agents such as soy isoflavones, resveratrol, curcumin, ascorbate, and alpha-tocopherol is discussed. The potential for these natural compounds to be combined with chemotherapy or radiotherapy for the more effective treatment of cancer are also reviewed. A proposed mechanism of action is discussed and an attempt is made to delineate which of the two activities of APE1/Ref-1 (DNA repair versus redox activation of cellular transcription factors) is responsible for the observed effects. The second manuscript by R. Rosati et al. reviews the role for dietary folate in the prevention of colorectal cancer. Data are presented which demonstrate that inhibition of DNA repair is protective in the development of preneoplastic colon lesions, both when folate is depleted and when it is not. This manuscript is a comprehensive review of the literature and provides a critical analysis of the experimental designs used in folate and colorectal cancer research. Two additional manuscripts detailing the ability of dietary agents to sensitize cancer cells to chemotherapy and radiotherapy are included in this special issue. An original research article by S. Duangmano et al. demonstrates that curcurbitacin B, a plant phytochemical, inhibited breast cancer cell proliferation in a dose-dependent manner and caused radiosensitization of human breast cancer cells via G2/M cell cycle arrest. Furthermore, an original research article by K. Sahin et al. demonstrate that genistein, a soy isoflavone, sensitizes cervical cancer cells to cisplatin via inhibition of NF-kappa B and Akt/mTOR cell signaling pathways. This special issue concludes with a report of a clinical study demonstrating the prevention of anthracycline-induced cardiac toxicity through supplementation with selenium in a group of pediatric cancer patients. Research efforts aimed at understanding the role of dietary agents and phytochemicals in cancer prevention and treatment are likely to yield high-impact results that have the potential for immediate clinical applications. Furthermore, combination of phytochemicals and nutritional agents with therapies for advanced cancers, including radiotherapy and chemotherapy, would benefit from a complementary and safe approach using dietary agents to mitigate the adverse effects of these therapies on normal tissues while enhancing the therapeutic efficacy. Elucidation of the mechanisms of interaction between dietary agents and conventional cancer treatments will have a major impact on understanding the molecular mechanisms of cancer chemoprevention and will ultimately result in clinical use of dietary agents as an adjunct to standard cancer treatment. Julian J. Raffoul Omer Kucuk Fazlul H. Sarkar Gilda G. Hillman