Penn State College of Medicine, Penn State Hershey Cancer Institute, Hershey, PA 17033, USA.
Int J Cancer. 2010 Jul 1;127(1):230-8. doi: 10.1002/ijc.25033.
Hormone refractory prostate cancer poses a huge problem and standard of care chemotherapy has not been very successful. We used a novel strategy to combine properties of 2 well-studied class of compounds (selenium and COX-2 inhibitor) and examined the resulting effectiveness against prostate cancer. Bearing in mind that sulfonamide moiety and pyrazole ring is important for the proapoptotic activity of Celecoxib, we synthesized a selenium derivative, Selenocoxib-1, by modifying Celecoxib at position 3 of the pyrazole ring. The PAIII cells derived from a metastatic prostate tumor that arose spontaneously in a Lobund-Wistar (LW) rat were used to examine the efficacy of Selenocoxib-1 in vitro. In addition, human metastatic prostate cancer cells, PC-3M, were tested for antitumor effect of Selenocoxib-1 in vitro. The IC(50) in PAIII and PC-3M cells for Selenocoxib-1 was about 5 microM, while for Celecoxib it was more than 20 microM. Selenocoxib-1 induced apoptosis in a dose-dependent manner in the PAIII cells. COX-2 expression in PAIII cells was downregulated by Celecoxib and Selenocoxib-1 at 20 and 5 microM, respectively; the COX-2 activity was, however, not affected by Selenocoxib-1. Following treatment with Selenocoxib-1, PAIII cells resulted in dose-dependent decrease in HIF-1alpha, p-AKT and Bcl-2 levels. A reduction in weights was observed in subcutaneous tumors produced by PAIII cells pretreated with Selenocoxib-1 as compared to Celecoxib in LW rats. Further, following 1 week Selenocoxib-1 treatment of PAIII tumors resulted in significant reduction of tumor weights. This study demonstrates that Selenocoxib-1 is more effective against prostate cancer than Celecoxib.
激素难治性前列腺癌是一个巨大的问题，标准的化疗治疗并不十分成功。我们使用一种新的策略，将两种研究得很好的化合物（硒和 COX-2 抑制剂）的特性结合起来，并研究其对前列腺癌的治疗效果。考虑到磺酰胺基和吡唑环对于塞来昔布的促凋亡活性很重要，我们通过修饰塞来昔布的吡唑环的 3 位合成了一种硒衍生物，Selenocoxib-1。PAIII 细胞来源于自发性发生在 Lobund-Wistar（LW）大鼠中的转移性前列腺肿瘤，用于在体外研究 Selenocoxib-1 的疗效。此外，还测试了 Selenocoxib-1 对体外人转移性前列腺癌细胞 PC-3M 的抗肿瘤作用。Selenocoxib-1 在 PAIII 和 PC-3M 细胞中的 IC50 约为 5μM，而塞来昔布的 IC50 则大于 20μM。Selenocoxib-1 以剂量依赖的方式诱导 PAIII 细胞凋亡。Celecoxib 和 Selenocoxib-1 分别在 20 和 5μM 下调 PAIII 细胞中的 COX-2 表达；然而，Selenocoxib-1 不影响 COX-2 活性。用 Selenocoxib-1 处理后，PAIII 细胞中 HIF-1alpha、p-AKT 和 Bcl-2 水平呈剂量依赖性下降。与 LW 大鼠中的塞来昔布相比，用 Selenocoxib-1 预处理的 PAIII 细胞产生的皮下肿瘤的重量减少。此外，在 LW 大鼠中用 Selenocoxib-1 治疗 1 周后，PAIII 肿瘤的重量显著减轻。这项研究表明，Selenocoxib-1 比塞来昔布更有效地治疗前列腺癌。
