Abstract 878: Tanshinone-1 kills multidrug resistant tumor cells via reducing phospho-705-Stat3, potentiated by inhibiting secondary activation of signaling networks.

Abstract

Abstract One of the severest hurdles in cancer treatment is multidrug resistance (MDR), resulting from overexpression of drug transporters and/or deregulation of cellular signaling transduction. Persistent efforts have been made to find new agents and strategies to overcome MDR. MDR involves almost all clinically-used anticancer drugs with natural origins. In this study, however, we found that the natural product tanshinone-1 could circumvent MDR via reducing phospho-705-Stat3, potentiated by inhibiting secondary activation of signaling networks. Tanshinone-1 is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Tanshinone-1 displayed equipotent or even more potent cytotoxicity in three MDR tumor cell lines than in their corresponding parental cell lines. Tanshinone-1 induced apoptosis of the MDR cells by activating the intrinsic apoptotic pathway via disturbing mitochondria membrane potential and eliciting the cleavage of caspase-9 and caspase-3. The killing of MDR cells by tanshinone-1 was independent of drug transporters, but correlated tightly with its decreasing phospho-705-Stat3, highly possibly via activating certain phosphatase(s). The expression of the target genes of Stat3 including Mcl-1, cyclin D1, cIAP-2 and c-myc, was downregulated by the treatment with tanshinone-1. Knockdown of stat3 expression with specific small interfering RNA led to reduced sensitivity of the tested MDR cells to tanshinone-1. Treatment with Na3VO4, a pan inhibitor of phosphatases, completely reversed tanshinone-1-induced decrease of phospho-705-Stat3 and significantly lowered its cytotoxicity. Knockdown of phosphatase SHP-2 or PTP1B prevented reduction of phospho-705-Stat3 and induction of cell apoptosis driven by tanshinone-1. Further investigation revealed that tanshinone-1 activated signaling networks involving Akt, p38 and Erk pathways, possibly secondary to its reducing phospho-705-Stat3. Notably, simultaneous suppression of those pathways enhanced the cytotoxic effect of tanshinone-1 against the tested MDR cells. Cotreatment of the PI3K inhibitor PI103, the p38 inhibitor SB203580 and/or the MEK inhibitor AZD6244 with tanshinone-1 potentiated its apoptotic induction. However, PI103 and SB580203 appeared to show more potent synergism than AZD6244 when combined with tanshinone-1. Together, this study presents tanshinone-1 as an MDR-overcoming natural product, and more importantly, from our results, a therapeutic strategy of targeting signaling network(s) may evolve for MDR cancer therapy. Citation Format: Lei Xu, Jian-Ming Feng, Jia-Xin Li, Jin-Mei Zhu, Shan-Shan Song, Lin-Jiang Tong, Yi Chen, Fu-Lin Lian, Dong-Hai Lin, Jian Ding, Ze-Hong Miao. Tanshinone-1 kills multidrug resistant tumor cells via reducing phospho-705-Stat3, potentiated by inhibiting secondary activation of signaling networks. [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 878. doi:10.1158/1538-7445.AM2013-878