Abstract A33: Enhancement of thymidine phosphorylase downregulation by erlotinib enhances cytotoxicity affected by tamoxifen in human non-small cell lung cancer cells

Abstract

Tamoxifen is a triphenylethylene nonsteroidal antiestrogen used worldwide as an adjuvant chemotherapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen also could induce cytotoxicity in non-small cell lung cancer (NSCLC) cells have not been proved. In this study, tamoxifen treatment inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with tamoxifen decreased TP mRNA and protein levels in an AKT inactivation-dependent manner. Furthermore, expression of constitutively active AKT (AKT-CA) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells. In contrast, a combination of PI3K inhibitors (LY294002 or wortmannin) further decreased the TP expression and cell viability induced by tamoxifen. Moreover, knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and growth inhibition of tamoxifen. Erlotinib (Tarceva, OSI-774), an orally available inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for clinical use in the NSCLC therapy. Compared to each single treatment, the combining tamoxifen with erlotinib resulted in a synergistically inhibited the cell viability and cell growth, accompanied with the reduction of phospho-AKT, phosph-ERK1/2, and TP protein levels. An enhancement of AKT or ERK1/2 activation by transfecting the cancer cells with constitutively active AKT or MKK1/2 expression vectors significantly restored the two drugs combination-reduced TP protein levels as well as cell viability. Taken together, our results suggest that the down-modulation of AKT and ERK1/2-mediated TP expression by erlotinib represents a key factor in enhancing the cytotoxic effects of tamoxifen in NSCLC cells. Citation Format: Yun-Wei Lin, Hsien-Chun Chiu, Jhan-Jhang Syu, Yun-Ting Jian, Chien-Yu Chen. Enhancement of thymidine phosphorylase downregulation by erlotinib enhances cytotoxicity affected by tamoxifen in human non-small cell lung cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A33. doi: 10.1158/1557-3125.RASONC14-A33