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.
Highlights
Chemotherapy is widely used to treat cancer, often with effective results
Clinical practice has shown that hepatocellular carcinoma (HCC) cells are less sensitive to chemotherapeutic drugs than many other cancers due to multi-drug resistance (MDR), which is characterized by tumor cell resistance, to a specific drug, and to other drugs with different structures and mechanisms [1]
We sought to characterize the effects of Ubenimex to elucidate molecular mechanisms that can reverse MDR in Hepatocellular carcinoma (HCC) and improve chemotherapy
Summary
Clinical practice has shown that hepatocellular carcinoma (HCC) cells are less sensitive to chemotherapeutic drugs than many other cancers due to multi-drug resistance (MDR), which is characterized by tumor cell resistance, to a specific drug, and to other drugs with different structures and mechanisms [1]. CD13, referred as Aminopeptidase N, is a widely expressed type II zinc-dependent metalloproteinase [3]. It promotes tumor angiogenesis, invasion, and metastasis in breast, ovarian, and anterior cancer cells by inducing enzymatic cleavage of polypeptide chains [4]. CD13+ cells in liver cancer transplants show higher proliferation ability and significantly greater resistance to Doxorubicin and 5-fluorouracil than CD13-cells [8]
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