A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma

• Published in: International journal of oncology Vol. 49; no. 1; pp. 89 - 98
• Main Authors: YAMASHITA, MASAFUMI, WADA, HIROSHI, EGUCHI, HIDETOSHI, OGAWA, HISATAKA, YAMADA, DAISAKU, NODA, TAKEHIRO, ASAOKA, TADAFUMI, KAWAMOTO, KOICHI, GOTOH, KUNIHITO, UMESHITA, KOJI, DOKI, YUICHIRO, MORI, MASAKI
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.07.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apoptosis; Apoptosis - drug effects; cancer stem cells; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; CD13 antigen; CD13 Antigens - antagonists & inhibitors; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Chemotherapy; Cisplatin - administration & dosage; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; Drug dosages; Drug Synergism; Drug therapy; Drug therapy, Combination; Flow cytometry; Fluorouracil - administration & dosage; Gene Expression Regulation, Neoplastic - drug effects; hepatocellular carcinoma; Hepatoma; Humans; Kinases; Leucine - administration & dosage; Leucine - analogs & derivatives; Leukemia; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Methods; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Observations; Patient outcomes; Phenylurea Compounds - administration & dosage; reactive oxygen species; Reactive Oxygen Species - metabolism; Signal transduction; Stem cells; Studies; Tumors; ubenimex
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3496

Cancer stem cells (CSCs) were reported to be involved in resistance to chemo/radiation therapy. We previously reported that CD13 was both a marker of CSCs and a candidate therapeutic target in HCC. In the present study, we explored the antitumor effect of a combined therapy, where ubenimex, a CD13 inhibitor, was combined with conventional anticancer drugs, fluorouracil (5-FU), cisplatin (CDDP), doxorubicin (DXR) and sorafenib (SOR), and we elucidated the mechanism of these combination therapies. We evaluated changes in the expression of CD13 before and after treatment with anticancer drugs and with or without ubenimex in the human HCC cell lines HuH7 and PLC/PRF/5. The interactions between the anticancer drugs and ubenimex were determined with isobologram analyses. We analyzed cell cycle, apoptosis, and intracellular reactive oxygen species (ROS) levels to explore the mechanisms of the combination therapies. In both cell lines, the expression of CD13 increased after a 72-h exposure to each anticancer drug alone (P<0.05), and the expression of CD13 decreased with ubenimex administration (P<0.05). Isobologram analyses indicated that ubenimex had synergistic effects with 5-FU, CDDP and DXR, and an additive effect with SOR. Cell cycle analyses showed that ubenimex decreased the proportion of cells in G0/G1. Ubenimex enhanced the effects of 5-FU, CDDP and DXR by increasing apoptosis and intracellular ROS levels. In combination therapies, ubenimex synergistically enhanced the antitumor effects of 5-FU, CDDP and DXR on cell cycle regulation and apoptosis induction in HCC cell lines. The effects of ubenimex were due to increased intracellular ROS levels.