| Prostate cancer is a significant problem in the Western world. However, the incidence and death due to this disease is less common in China and Japan where diets are rich in vitamin D and soy. Extensive epidemiological and laboratory data provide evidence for the growth inhibitory actions of vitamin D and genistein, a soy isoflavone. Here, we conducted experiments to determine the actions of these compounds when used alone and in combination, on prostate cancer cell lines as well as on primary human prostatic epithelial cells (HPECs) derived from benign and cancer prostate tissue.; The enzyme, 25-hydroxyvitamin D 1alpha-hydroxylase (1αOHase), converts the non-calcemic prohormone, 25-hydroxyvitamin D3 [25OHD3 ] to 1,25 dihydroxyvitamin D3 [1,25(OH)2D 3], the hormonally active form of vitamin D. We demonstrated the presence of this enzyme in benign and cancer prostate tissue as well as in HPECs derived from these tissues. Both benign and cancer tissue derived HPECs are growth inhibited by 25OHD3 and 1,25(OH)2D3. Treatment of HPECs and LNCaP cells with both forms of vitamin D causes a G0/1 cell cycle arrest. The presence of 1αOHase, and that cancer derived HPECs are growth inhibited by 25OHD3 makes this non calcemic compound potentially useful in prostate cancer chemoprevention.; Subsequently, we determined that genistein is also a potent growth inhibitor of benign and cancer derived HPECs. Additionally, HPECs are more sensitive to growth inhibition by genistein than are prostate cancer cell lines such as LNCaP and PC-3. Genistein inhibits growth of HPECs by causing a G 2M arrest, while in LNCaP cells genistein causes a G0/1 arrest. When used in combination, genistein synergizes with 1,25(OH)2D 3 to inhibit growth of HPECs and LNCaP cells. Genistein also synergizes with 25OHD3 to inhibit growth of HPECs. At doses used in our experiments neither genistein nor vitamin D metabolites caused apoptosis.; We then examined the molecular actions of these compounds. In combination, 1,25(OH)2D3 and genistein caused a cooperative increase in protein levels of the cyclin dependent kinase inhibitor p21 in LNCaP cells. Subsequently, the expression of p21 was “knocked-down” in LNCaP cells using siRNA. When these cells were treated with 1,25(OH)2D 3 and genistein both alone and in combination, growth inhibition was not significantly different from that of untreated cells. Therefore, the ability of these compounds to inhibit growth is dependent on the presence of p21. Additionally, in combination, 1,25(OH)2D3 and genistein caused a cooperative increase in protein levels of the vitamin D receptor (VDR), from 4 until 96 hours after treatment.; We conclude that 1,25(OH)2D3 and genistein by cooperatively upregulating both p21 and VDR cause a synergistic growth inhibition of prostate cancer cells, potentially by enhancing the growth inhibitory actions of 1,25(OH) 2D3. Therefore, these compounds could be used in prostate cancer chemoprevention or as adjuvants in prostate cancer therapy. |
