Therapeutic effects of survivin dominant negative mutant in a mouse model of prostate cancer

Pan, Li
Peng, Xing-Chen
Leng, Fei
Yuan, Qing-Zhong
Shan, Yan
Yu, Dan-Dan
Li, Zhi-Yong
Chen, Xiang
Xiao, Wen-Jing
Wen, Yuan
Ma, Tian-Tai
Yang, Li
Mao, Yong-Qiu
Yang, Han-Shuo
Wei, Yu-Quan
Wang, Chun-Ting

¹State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Chengdu, Sichuan, People's Republic of China
²State Key Laboratory of Biotherapy, West China Hospital, School of Life Science, Sichuan University, Chengdu, Sichuan, People's Republic of China

Received: 30 October 2009/Accepted: 19 February 2010/Published online: 9 March 2010

L. Pan, X.-C. Peng and F. Leng have equally contributed to the present study.

Journal of Cancer Research and Clinical Oncology 137(1):p 19-28, January 2011. | DOI: 10.1007/s00432-010-0855-2

Abstract

Purpose

Patients with localized prostate cancer can usually achieve initial response to conventional treatment. However, most of them will inevitably progress to advanced disease stage. There is a clear need to develop innovative and effective therapeutics for prostate cancer. Mouse survivin T34A (mS-T34A) is a phosphorylation-defective Thr34 → Ala dominant negative mutant, which represents a potential promising target for cancer gene therapy. This study was designed to determine whether mS-T34A plasmid encapsuled by DOTAP-chol liposome (Lip-mS) has the anti-tumor activity against prostate cancer, if so, to further investigate the possible mechanisms.

Methods

In vitro, TRAMP-C1 cells were transfected with Lip-mS and examined for apoptosis by PI staining and flow cytometric analysis. In vivo, subcutaneous prostate cancer models were established in C57BL/6 mice, which were randomly assigned into three groups to receive i.v. administrations of Lip-mS, pVITRO2-null plasmid complexed with DOTAP-chol liposome (Lip-null) or normal saline every 2 days for eight doses. Tumor volume was measured. Tumor tissues were inspected for apoptosis by TUNEL assay. Microvessel density (MVD) was determined by CD31 immunohistochemistry. Alginate-encapsulated tumor cell test was conducted to evaluate the treatment effect on angiogenesis.

Results

Administration of Lip-mS resulted in significant inhibition in the growth of mouse TRAMP-C1 tumors. The anti-tumor response was associated with increased tumor cell apoptosis and decreased microvessel density.

Conclusions

The present study may be of importance in the exploration of the potential application of Lip-mS in the treatment of a broad spectrum of tumors.