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Cancer chemoprevention by phytochemicals may be one of the most feasible approaches for cancer control. Phytochemicals obtained from vegetables, fruits, spices, teas, herbs and medicinal plants, such as terpenoids and other phenolic compounds, have been proven to suppress experimental carcinogenesis in various organs in pre-clinical models. Recent studies have indicated that mechanisms underlying chemopreventive potential may be a combination of antioxidant, anti-inflammatory, immune-enhancing, and hormone modulation effects, with modification of drug metabolizing enzymes, influence on cell cycle and cell differentiation, induction of apoptosis, suppression of proliferation and angiogenesis playing roles in the initiation and secondary modification stages of neoplastic development. Specific features of prostate cancer, such as high prevalence and long latency period provides ample opportunities for chemopreventive agents to work at various stages of disease progression. Finally, suitable populations with appropriate risk factors, including the presence of pre-malignant lesions and genetic predispositions, need to be well characterized for future chemopreventive interventions. Here we review naturally occurring dietary terpenoids as useful agents for prostate cancer chemoprevention with reference to their classes and sources.
PMCID: PMC4019960  PMID: 18508447
Terpenoids; cancer chemoprevention; biomarkers; prostate cancer
2.  Betulinic Acid Suppresses Constitutive and TNFα-induced NF-κB Activation and Induces Apoptosis in Human Prostate Carcinoma PC-3 Cells 
Molecular carcinogenesis  2008;47(12):964-973.
Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-κB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-κB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-κB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-κB/p65. BetA-mediated NF-κB inhibition involved decreased IKK activity and phosphorylation of IκBα at serine 32/36 followed by its degradation. Reporter assays revealed that NF-κB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFα-induced activation of NF-κB via the IκBα pathway, thereby sensitizing the cells to TNFα-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-κB activation and supports the rationale for targeting NF-κB through combination protocols with BetA in androgen-refractory prostate cancer.
PMCID: PMC2864721  PMID: 18444250
transcription factor; betulinic acid; IκBα; IKK; prostate cancer
3.  d-Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis 
Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d-Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d-limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer.
Materials and Methods:
Human prostate carcinoma DU-145 and normal prostate epithelial PZ-HPV-7 cells were treated with various concentrations of d-limonene, docetaxel or a combination of both, and cell viability was determined by MTT assay. Intracellular reactive oxygen species (ROS), reduced glutathione (GSH) and caspase activity were measured. Apoptosis and apoptosis-related proteins were studied by enzyme-linked immunosorbent assay and Western blotting, respectively.
d-Limonene and docetaxel in combination significantly enhanced the cytotoxicity to DU-145 cells than PZ-HPV-7 cells. Exposure of DU-145 cells to a combined d-limonene and docetaxel resulted in higher ROS generation, depletion of GSH, accompanied by increased caspase activity than docetaxel alone. It also triggered a series of effects involving cytochrome c, cleavages of caspase-9, 3 and poly (ADP-ribose) polymerase, and a shift in Bad:Bcl-xL ratio in favor of apoptosis. Apoptotic effect was significantly blocked on pretreatment with N-acetylcystein, indicating that antitumor effect is initiated by ROS generation, and caspase cascades contribute to the cell death.
Our results show, for the first time, that d-limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d-Limonene could be used as a potent non-toxic agent to improve the treatment outcome of hormone-refractory prostate cancer with docetaxel.
PMCID: PMC2699604  PMID: 19465777
Apoptosis; d-limonene; docetaxel; DU-145; prostate cancer; reactive oxygen species

Results 1-3 (3)