Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor KB (NF-KB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-KB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-KB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 Mmol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 Mmol/ L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-KB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-KB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-KB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-KB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers. (Cancer Res 2005; 65(15): 6934-42)

We report the synthesis of novel 1:1 Schiff base copper complexes of quinoline-2-carboxaldehyde showing dose-dependent, antiproliferative, and proapoptotic activity in PC-3 and LNCaP prostate cancer cells. We found that quinoline thiosemicarbazone 2 (FPA-137) was the most potent and inhibited proteosome activity in intact human prostate cancer PC-3 and LNCaP cells (IC50 of 4 and 3.2 microM, respectively) compared to clioquinol and pyrrolidine dithiocarbamate (IC50 of 10 and 20 microM), supporting the novelty of 2.

Despite the initial efficacy of androgen deprivation therapy, most patients with advanced prostate cancer eventually progress to hormone-refractory prostate cancer, for which there is no curative therapy. Previous studies from our laboratory and others have shown the antiproliferative and proapoptotic effects of 3,3 ¶-diindolylmethane (DIM) in prostate cancer cells. However, the molecular mechanism of action of DIM has not been investigated in androgen receptor (AR)-positive hormoneresponsive and -nonresponsive prostate cancer cells. Therefore, we investigated the effects of B-DIM, a formulated DIM with greater bioavailability, on AR, Akt, and nuclear factor KB (NF-KB) signaling in hormone-sensitive LNCaP (AR+) and hormone-insensitive C4-2B (AR+) prostate cancer cells. We found that B-DIM significantly inhibited cell proliferation and induced apoptosis in both cell lines. By Akt gene transfection, reverse transcription-PCR, Western blot analysis, and electrophoretic mobility shift assay, we found a potential crosstalk between Akt, NF-KB, and AR. Importantly, B-DIM significantly inhibited Akt activation, NF-KB DNA binding activity, AR phosphorylation, and the expressions of AR and prostate-specific antigen, suggesting that B-DIM could interrupt the crosstalk. Confocal studies revealed that B-DIM inhibited AR nuclear translocation, leading to the down-regulation of AR target genes. Moreover, B-DIM significantly inhibited C4-2B cell growth in a severe combined immunodeficiency-human model of experimental prostate cancer bone metastasis. These results suggest that B-DIM-induced cell proliferation inhibition and apoptosis induction are partly mediated through the downregulation of AR, Akt, and NF-KB signaling. These observations provide a rationale for devising novel therapeutic approaches for the treatment of hormone-sensitive, but more importantly, hormone-refractory prostate cancer by using B-DIM alone or in combination with other therapeutics.