BERKELEY, CA (UroToday.com) - Epidemiological evidence suggesting that cancer rates can be influenced by dietary factors has led to extensive efforts to identify plant-derived compounds that could be developed as chemopreventive agents aimed at preventing or reversing carcinogenesis or cancer progression. One such compound we and others have been studying is apigenin (4', 5, 7,-trihydroxyflavone), a plant flavone present abundantly in common vegetables, herbs, and spices including parsley, celery, and chamomile. Apigenin has anti-carcinogenic and anti-proliferative effects in animal cancer models and is a potent inhibitor of several kinases involved in the development and progression of cancer, including phosphatidylinositol-3 kinase (PI3K)-Akt, mitogen-activated protein kinases, casein kinase-2, and focal adhesion kinase. We have shown previously that apigenin inhibits proliferation of human prostate cancer cell lines and xenografts and suppresses prostate carcinogenesis in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which express the SV40 T and t antigens specifically in the prostate epithelium. Male TRAMP mice spontaneously develop multiple-stage prostatic adenocarcinoma that mimics the progression of human prostate cancer, viz. development of low-grade prostatic intraepithelial neoplasia (PIN) at about 6 weeks of age, progression to high-grade PIN by 12 weeks, development of focal adenocarcinoma between 12 and 18 weeks, progression to poorly differentiated carcinoma by 28 weeks, and occasional metastases to lungs, lymph nodes, liver, and bone after 28 weeks.
Here, we have shown that daily oral intake of apigenin by TRAMP mice from 8 to 28 weeks of age, at doses equivalent to human consumption of a healthy diet, markedly inhibited the progression of adenocarcinoma in TRAMP mice and completely prevented distant organ metastases, while inhibiting phosphorylation of Akt and the forkhead transcription factor FoxO3a in the prostate. FoxO3a is a tumor suppressor negatively regulated by Akt phosphorylation, and we recently showed that treatment of TRAMP mice with a peptide that inhibited FoxO3a activity resulted in accelerated progression of prostate cancer. Consistent with the inhibition of FoxO3a phosphorylation by apigenin, we found markedly decreased binding of FoxO3a to Akt and the 14-3-3 chaperone protein, increased nuclear localization of FoxO3a, and increased expression of FoxO-responsive proteins Bim and p27/Kip1 in the prostate in apigenin-treated TRAMP mice.
No loss of weight or signs of toxicity were observed during the entire period of the experiment in mice given apigenin compared with vehicle-treated control TRAMP mice. Overall, these results strongly suggest that apigenin effectively suppressed prostate cancer progression, at least in part by inhibiting the PI3K/Akt/FoxO-signaling pathway.
Prostate cancer is an attractive target for chemoprevention in men because of its typical long latency period between pre-malignant lesions and clinically evident cancer. We found previously that FoxO3a is heavily phosphorylated and retained in the cytoplasm in prostate cancer patient specimens, in association with disease progression. Based on these findings it would be worthwhile to determine the efficacy of apigenin through a well-designed clinical trial.
Sanjay Gupta as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Urology, Case Western Reserve University, Cleveland, Ohio USA
Department of Nutrition, Case Western Reserve University, Cleveland, Ohio USA
The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio USA
Case Comprehensive Cancer Center, Cleveland, Ohio USA