Abstract
Multidrug resistance (MDR) of hepatocellular carcinoma is a serious problem. Although CD13 is a biomarker in human liver cancer stem cells, the relationship between CD13 and MDR remains uncertain. This study uses liver cancer cell model to understand the role of CD13 in enhancing the cytotoxic effect of chemotherapy agents. Cytotoxic agents can induce CD13 expression. CD13 inhibitor, bestatin, enhances the antitumor effect of cytotoxic agents. Meanwhile, CD13-targeting siRNA and neutralizing antibody can enhance the cytotoxic effect of 5-fluorouracil (5FU). CD13 overexpression increases cell survival upon cytotoxic agents treatment, while the knockdown of CD13 causes hypersensitivity of cells to cytotoxic agents treatment. Mechanistically, the inhibition of CD13 leads to the increase of cellular reactive oxygen species (ROS). BC-02 is a novel mutual prodrug (hybrid drug) of bestatin and 5FU. Notably, BC-02 can inhibit cellular activity in both parental and drug-resistant cells, accompanied with significantly increased ROS level. Moreover, the survival time of Kunming mice bearing H22 cells under BC-02 treatment is comparable to the capecitabine treatment at maximum dosage. These data implicate a therapeutic method to reverse MDR by targeting CD13, and indicate that BC-02 is a potent antitumor compound.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer type and the third leading cause of cancer-related deaths worldwide (Mlynarsky et al, 2015)
CD13 upregulation induced by cytotoxic agent treatments demonstrated that CD13 may contribute to cell resistance to anticancer drugs
The increased CD13 expression may protect cells from cytotoxic agents, and CD13 inhibitor bestatin enhances the cytotoxic effect of anticancer drugs
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer type and the third leading cause of cancer-related deaths worldwide (Mlynarsky et al, 2015). Prognosis remains poor due to the low percentage of patients with HCC eligible for surgery (9–29%) (Tsurusaki and Murakami, 2015), high tumor recurrence rates after resection (60%) (Cheng et al, 2005), and limited benefit of conventional chemotherapy (Cao et al, 2012; Deng et al, 2015). MDR is one of the major causes of chemotherapeutic failure in HCC therapy. Exploring more effective therapeutic strategies for patients with HCC is urgently needed. Increasing clinical trials have proposed that combination therapy may provide new strategy for chemo-resistance in patients with advanced HCC (Alves et al, 2011; Cervello et al, 2012; Shin and Chung, 2013)
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