Antitumor Effects of Thalidomide Analogs in Human Prostate Cancer Xenografts Implanted in Immunodeficient Mice

Abstract

Purpose: Thalidomide has demonstrated clinical activity in various malignancies including androgen-independent prostate cancer. The development of novel thalidomide analogs with better activity/toxicity profiles is an ongoing research effort. Our laboratory previously reported the in vitro antiangiogenic activity of the N-substituted thalidomide analog CPS11 and the tetrafluorinated analogs CPS45 and CPS49. The current study evaluated the therapeutic potential of these analogs in the treatment of prostate cancer in vivo.Experimental Design: Severely combined immunodeficient mice bearing s.c. human prostate cancer (PC3 or 22Rv1) xenografts were treated with the analogs at their maximum tolerated doses. Tumors were then excised and processed for ELISA and CD31 immunostaining to determine the levels of various angiogenic factors and microvessel density (MVD), respectively.Results: CPS11, CPS45, and CPS49 induced prominent and modest growth inhibition in PC3 and 22Rv1 tumors, respectively. Thalidomide had no effect on tumor growth in either xenograft. Vascular endothelial growth factor and basic fibroblast growth factor levels were not significantly altered by any of the thalidomide analogs or thalidomide in both PC3 and 22Rv1 tumors. CPS45, CPS49, and thalidomide significantly reduced PC3 tumor platelet-derived growth factor (PDGF)-AA levels by 58 -82% (P < 0.05). Interestingly, treatment with the analogs and thalidomide resulted in differential down-regulation (>1.5-fold) of genes encoding PDGF and PDGF receptor isoforms as determined by DNA microarray analysis. Intratumoral MVD of 22Rv1 xenografts was significantly decreased by CPS45 and CPS49. CPS49 also reduced MVD in PC3 xenografts.Conclusions: Thalidomide analogs CPS11 and 49 are promising anti-cancer agents. PDGF signaling pathway may be a potential target for these thalidomide analogs. Detailed microarray and functional analyses are under way with the aim of elucidating the molecular mechanism(s) of action of these thalidomide analogs.

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

“…The antitumor activity is similar to that seen with prostate cancer cell lines, where treatment with CPS11 and CPS49 has led to regression of subcutaneous implanted tumors in SCID mice. 13 Although CPS11 was more potent than CPS49 against prostate cancer, our findings suggest that CPS49 is more potent in the setting of MM.…”

“…7 CPS49 can decrease intratumoral vascularity in xenograft models of prostate cancer via inhibition of PDGF. 13 Ongoing studies in animal models of MM will evaluate whether antiangiogenesis correlates with MM responses. Finally, immunomodulation contributes to the anti-MM activity of thalidomide and many of its analogs, 20 and ongoing studies are evaluating the effects of CPS11 and CPS49 on NK and T cells.…”

Antioxidant Effects of Gamma-oryzanol on Human Prostate Cancer Cells

“…Recent reports examined to demonstrate the possibility to using gamma-oryzanol to treat cancer including prostate cancer (Ng and Figg, 2003). The imbalance of oxidant-antioxidant system resulting in increased oxidative stress was reported as an important feature of this type of cancer (Battisti et al, 2011;Tangjitjaroenkun et al, 2012).…”

Licorice Extract Does Not Impair the Male Reproductive Function of Rats

“…Therefore, it was proposed that licorice could cause the deficiency of serum testosterone, leading to sexual dysfunction or decline of libido in men [1,2]. However, the testosterone-reducing effect of licorice in males is controversial, since the results of Armanini et al [1,2] have not been reproduced by other investigators [16,25].…”