Drug resistance causes a serious limitation for the chemotherapy of multiple myeloma. Combination cancer therapy is one of attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin (a major compound in Angelica gigas) and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Concurrent treatment of decursin and doxorubicin significantly exerted significant cytotoxicity, while doxorubicin or decursin alone had no cytotoxic effect at physiologically relevant concentrations in signal transducer and activator of transcription 3 (STAT3) positive cell lines such as U266 and RPMI8226 cells and also STAT3 negative cell line MM.1S cells. We further demonstrated that the loss of the viability of the cells co-treated with decursin and doxorubicin was due to the induction of apoptosis. Combination treatment of doxorubicin and decursin enhanced the activation of caspapse-9 and 3, the cleavage of poly (ADP-ribose) polymerase (PARP) and sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment of doxorubicin and decursin downregulated the phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream S6K1 and activated the phosphorylation of extracellular signal regulated kinase (ERK) in three multiple myeloma cells. Furthermore, the combined treatment of doxorubicin and decursin reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3 and Src, activated SHP-2 and attenuated the expression of cyclind-D and survivin in STAT3 positive U266 cells. Conversely, the broadly-acting tyrosine phosphatases inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activatio induced by combine treatment of doxorubicin and decursin in U266 cells.

Citation Format: Duck-Beom Jung, Soo-Jin Jeong, Hee-Young Kwon, Ji Hoon Jung, Eunjung sohn, Eun Ah Sin, Ji-Hyun Kim, Sun-Mi Cho, Miyong Yun, Hyo-jung Lee, Sung Hoon Kim. Decursin and doxorubicin are in synergy for the induction of apoptosis via STAT3 and/or mTOR pathways in human multiple myeloma cells. [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 836. doi:10.1158/1538-7445.AM2013-836

©2013 American Association for Cancer Research
2013