Abstract 986: Sildenafil potentiates the anticancer activity of paclitaxel in ABCB1-mediated multidrug resistance xenograft model

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 8_Supplement; p. 986
• Main Authors: Sodani, Kamlesh, Tiwari, Amit K., Dai, Chun-ling, Abuznait, Alaa H., Xiao, Zhi-jie, Kaddouni, Amal, Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: 15.04.2013
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-986

Abstract The multidrug resistance (MDR) phenotype caused by the overexpression of ATP-binding cassette (ABC) transporters promotes the cellular efflux of a variety of anticancer drugs that may lead to cancer treatment failure. Previous in vitro studies from our group reported sildenafil, a PDE-5 inhibitor, could significantly block the function of ABCB1/P-glycoprotein and reverse ABCB1/P-glycoprotein-mediated MDR. In the current study we investigated the effect of sildenafil on the ABCB1-mediated MDR in vivo. To determine this effect we developed ABCB1-xenograft nude muse model using ABCB1 overexpressing KB-C2 cell line. We found that sildenafil significantly enhanced the chemotherapeutic response of paclitaxel in the ABCB1-xenograft nude mouse model. The combination treatment with sildenafil and paclitaxel attenuated the tumor growth synergistically. In addition, there was no visible toxicity, weight loss or other gross phenotypic changes with combination treatment. The positive effects of sildenafil can be attributed to inhibition of ABCB1-mediated drug efflux. This phenomenon was further supported by increased concentrations of paclitaxel in ABCB1-overexpressing tumors in the combination treatment group compared to paclitaxel alone. In addition, pharmacokinetic analysis showed increase in the plasma paclitaxel concentration in the combination group. These beneficial actions of sildenafil can be considered as viable option for combination therapy with the clinical anticancer drugs that succumb to ABCB1-mediated insensitivity. Citation Format: Kamlesh Sodani, Amit K. Tiwari, Chun-ling Dai, Alaa H. Abuznait, Zhi-jie Xiao, Amal Kaddouni, Zhe-Sheng Chen. Sildenafil potentiates the anticancer activity of paclitaxel in ABCB1-mediated multidrug resistance xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 986. doi:10.1158/1538-7445.AM2013-986