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Int J Biol Sci. 2019 Jan 24;15(3):668-679. doi: 10.7150/ijbs.30168. eCollection 2019.

Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A.

Wang Z1,2, Wang C1,2, Zuo D1,2, Zhang T2, Yin F1,2, Zhou Z2, Wang H2, Xu J1,2, Mao M2, Wang G2, Hua Y1,2, Sun W1,2, Cai Z1,2.

Author information

1
Department of Orthopaedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
2
Shanghai Bone Tumor Institution, Shanghai, China.

Abstract

Osteosarcoma (OS) is the most common primary bone malignancy in adolescents. One major obstacle for current OS treatment is drug-resistance. Raddeanin A (RA), an oleanane-type triterpenoid saponin, exerts anti-tumor effects in several tumor models, but the effect of RA in human drug-resistant OS remained to be elucidated. In the present study, we investigated the anti-tumor effects of RA in both drug-sensitive and drug-resistant OS cells and its underlying mechanism. RA inhibited cell proliferation and colony formation and induced apoptotic cell death in a dose-dependent manner in both drug-sensitive and drug-resistant cells. Moreover, RA exposure resulted in the inhibition of interleukin-6 (IL-6)-induced JAK2/STAT3 signaling pathway activation and target gene expression in both drug-sensitive and drug-resistant cells. Meanwhile, we observed significantly increased MDR1 and STAT3 expression in drug-resistant OS cells compared with parental cells. STAT3 overexpression promoted chemo-resistance and MDR1 protein expression in both drug-sensitive OS cells and drug-resistant OS cells, while inhibiting STAT3 with siRNA sensitized OS cells to doxorubicin treatment. In addition, RA synergistically increased doxorubicin toxicity by increasing its cellular uptake, ablating efflux and downregulating MDR1 in drug-resistant cells with attenuation of STAT3 Phosphorylation. Finally, RA suppressed in vivo tumor growth and induced apoptosis in nude mouse using drug-resistant OS tibia orthotopic model. Taken together, RA is a promising potential therapeutic for the treatment of doxorubicin resistance in OS.

KEYWORDS:

MDR1; Raddeanin A; STAT3; drug-resistance; osteosarcoma

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