Ubenimex suppresses Pim-3 kinase expression by targeting CD13 to reverse MDR in HCC cells
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Qie Guo1, Zhong-Guo Sui1, Wen Xu1, Xiang-Hua Quan1, Jia-Lin Sun1, Xiao Li1, Hong-Yan Ji1 and Fan-Bo Jing1
1Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China
Fan-Bo Jing, email: [email protected]
Keywords: Ubenimex, hepatocellular carcinoma, multi-drug resistance, CD13, Pim-3 kinase
Received: February 07, 2017 Accepted: July 18, 2017 Published: August 10, 2017
Hepatocellular carcinoma (HCC) is one of the most serious cancers, with rapid progression and high mortality. However, chemotherapy of HCC is hindered by multi-drug resistance (MDR). It is urgent, therefore, to explore new approaches for overcoming MDR of HCC cells. Ubenimex, an inhibitor of CD13, has been used as an immuno-enhancer for treating hematological neoplasms and other solid tumors. Here, we demonstrate that Ubenimex can also reverse MDR in the HCC cell lines HepG2/5-FU and Bel7402/5-FU. Ubenimex inhibits the expression of the proto-oncogene, Pim-3, which is accompanied by decreased expression of BCL-2 and BCL-XL, decreased phosphorylation of Bad, and increased tumor apoptosis.
Moreover, Ubenimex decreases expression of the MDR-associated proteins P-gp, MRP3 and MRP2 to enhance intracellular accumulation of Cisplatin, for which down-regulation of Pim-3 is essential. Our results reveal a previously uncharacterized function of Ubenimex in mediating drug resistance in HCC, which suggests that Ubenimex may provide a new strategy to reverse MDR and improve HCC sensitivity to chemotherapeutic drugs via its effects on Pim-3.
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