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Research Articles: Therapeutics, Targets, and Development

Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: induction of apoptosis through inactivation of nuclear factor B

¹ College of Pharmacy, ² School of Science Education, and ³ CBITRC, Chungbuk National University, 48 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, Korea; ⁴ College of Oriental Medicine, Kyungwon University, San 65 Bokjeong-dong, Sujeong-gu, Seongnam, Gyeonggii, Korea; and ⁵ College of Pharmacy, Woosuk University, San 65 Bokjeong-dong, Sujeong-gu, Wanju, Cheonbuk, Korea

Requests for reprints: Jin Tae Hong, College of Pharmacy, Chungbuk National University, 48 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 Korea. Phone: 82-43-261-2813; Fax: 82-43-268-2732. E-mail: jinthong{at}chungbuk.ac.kr

Abstract

We investigated whether the snake venom toxin (SVT) from Vipera lebetina turanica inhibits cell growth of human prostate cancer cells by inducing apoptosis and also studied possible signaling pathways involved in this cell death. SVT inhibited growth of PC-3 and DU145 cells, androgen-independent prostate cancer cells, but not LNCaP cells, a human androgen-dependent prostate cancer cell. Cells were arrested in the G₂-M phase by SVT with a concomitant decrease in the expression of the G₂-M phase regulatory protein cyclin B1 and were also arrested in the G₁-S phase with decreasing expression of cyclin-dependent kinase 4, cyclin D1 and cyclin E. In addition to the growth-inhibitory effect, SVT increased the induction of apoptotic cell death. Untreated PC-3 cells show high DNA binding activity of nuclear factor B (NF-B), an antiapoptotic transcriptional factor, but this was inhibited by SVT and accompanied by a significant inhibition of p50 translocation into the nucleus, as well as phosphorylation of inhibitory B. Consistent with the induction of apoptosis and inhibition of NF-B, this toxin increased the expression of proapoptotic proteins such as p53, Bax, caspase-3, and caspase-9, but down-regulated antiapoptotic protein Bcl-2. However, SVT did not show an inhibitory effect on cell growth and caspase-3 activity in cells carrying mutant p50 and inhibitory B kinase plasmids. Confocal microscopy analysis showed that SVT is taken up into the nucleus of the cells. These findings suggest that a nanogram concentration range of SVT from V. lebetina turanica could inhibit hormone-refractory human prostate cancer cell growth, and the effect may be related to NF-B signal–mediated induction of apoptosis. [Mol Cancer Ther 2007;6(2):675–83]

Grant support: Regional Research Centers Program of the Ministry of Education and Human Resources Development in Korea.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 1/06; revised 11/21/06; accepted 12/21/06.