The marked difference in the incidence of prostate cancer (CaP) among several regions of the world suggest that dietary factors may influence the biological process related to prostate carcinogenesis. Because CaP is the most common and one of the leading causes of cancer-related deaths in American males, to reduce the incidence of this disease, chemoprevention through dietary intervention appears to be a practical and encouraging approach. CaP is known to undergo a transition from an early 'androgen-sensitive' form of cancer to a late (metastatic) 'androgen-insensitive' cancer, and at the time of clinical diagnosis most CaP's represent a mixture of androgen-sensitive and androgen-insensitive cells. Therefore, the key to the control of CaP appears to lie in the elimination of both types of cells through mechanism-based intervention approaches. Epidemiological studies suggest that high consumption of fruits and vegetables is associated with a reduced risk of CaP. These studies are consistent with the observations that Asian men who consume low fat, high-fiber diet rich in flavonoids have lowest CaP incidence in the world. Laboratory studies in cell culture systems have demonstrated that apigenin, a plant flavonoid abundantly present in fruits and vegetables afford protection against many types of human cancers. Consistent with this notion in our preliminary studies we demonstrated that apigenin results in I) selective response of normal versus prostate carcinoma cells, ii) inhibition of cell growth, iii) induction of apoptosis, and iii) GO-Gl-phase arrest of cell cycle, in both androgen-dependent LNCaP and androgen- independent DU145 human prostate carcinoma cells. The present proposal capitalizes on these novel findings and is designed to investigate the effect of oral consumption of apigenin on the prostate tumorigenesis under in viva situations. To accomplish this goal, we will employ the well-accepted model of athymic nude mice implanted with androgen-independent PC-3 and androgen-dependent 22Rvl human prostate tumor cells. The hypothesis to be tested in this proposal is that apigenin will impart cancer-preventive and possibly cancer-therapeutic effects by modulating cell cycle- and apoptotic- machinery of CaP cells irrespective of their androgen association. A corollary to this hypothesis that will be tested in this proposal is that oral consumption of apigenin will reduce the levels of serum prostate specific antigen (PSA), possibly by modulating the androgen receptor in athymic nude mice transplanted with androgen-sensitive human prostate carcinoma cells. These studies could be considered as a starting point for an expanded program for the development of apigenin as a promising agent against CaP in humans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Shukla, Sanjeev; Gupta, Sanjay (2009) Apigenin suppresses insulin-like growth factor I receptor signaling in human prostate cancer: an in vitro and in vivo study. Mol Carcinog 48:243-252
Shukla, Sanjeev; Gupta, Sanjay (2008) Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation. Free Radic Biol Med 44:1833-45
Kaur, Parminder; Shukla, Sanjeev; Gupta, Sanjay (2008) Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study. Carcinogenesis 29:2210-7
Shukla, Sanjeev; Maclennan, Gregory T; Hartman, Douglas J et al. (2007) Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer 121:1424-32
Shukla, Sanjeev; Gupta, Sanjay (2007) Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle 6:1102-14
Shukla, Sanjeev; MacLennan, Gregory T; Flask, Chris A et al. (2007) Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. Cancer Res 67:6925-35
Shukla, Sanjeev; Gupta, Sanjay (2006) Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther 5:843-52
Shukla, Sanjeev; Mishra, Anil; Fu, Pingfu et al. (2005) Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J 19:2042-4
Shukla, Sanjeev; Gupta, Sanjay (2005) Dietary agents in the chemoprevention of prostate cancer. Nutr Cancer 53:18-32
Shukla, Sanjeev; Gupta, Sanjay (2004) Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol Carcinog 39:114-26

Showing the most recent 10 out of 13 publications