Ubenimex suppresses Pim-3 kinase expression by targeting CD13 to reverse MDR in HCC cells

Abstract

// Qie Guo 1 , Zhong-Guo Sui 1 , Wen Xu 1 , Xiang-Hua Quan 1 , Jia-Lin Sun 1 , Xiao Li 1 , Hong-Yan Ji 1 and Fan-Bo Jing 1 1 Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China Correspondence to: Fan-Bo Jing, email: jingbf178@sina.com Keywords: Ubenimex, hepatocellular carcinoma, multi-drug resistance, CD13, Pim-3 kinase Received: February 07, 2017     Accepted: July 18, 2017     Published: August 10, 2017 ABSTRACT 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.