3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells

• Published in: PloS one 2017-03, Vol.12 (3), p.e0174271-e0174271
• Main Authors: Lee, Minjong, Jo, Ara, Lee, Seulki, Kim, Jong Bin, Chang, Young, Nam, Joon Yeul, Cho, Hyeki, Cho, Young Youn, Cho, Eun Ju, Lee, Jeong-Hoon, Yu, Su Jong, Yoon, Jung-Hwan, Kim, Yoon Jun
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Acid production; Activation; Algae; Alkylation; Analysis; Angiogenesis; Animal models; Anion channels; Anoikis; Anoikis - drug effects; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antioxidants; Antitumor activity; Apoptosis; Argonaute 2 protein; Arsenic; Arsenic trioxide; Autografts; Biology and Life Sciences; Biotechnology; Breast; Buthionine Sulfoximine - pharmacology; Buthionine Sulfoximine - therapeutic use; Cancer; Cancer metastasis; Carcinoma, Hepatocellular - drug therapy; Care and treatment; Cell death; Chemotherapy; Comparative analysis; Cytotoxicity; Drug resistance; Epithelial-Mesenchymal Transition - drug effects; Fungi; Gene silencing; Hep G2 Cells; Hepatocellular carcinoma; Humans; Liver cancer; Liver Neoplasms - drug therapy; Lymphoma; Medicine; Medicine and Health Sciences; Metabolism; Neurodegenerative diseases; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Niacinamide - therapeutic use; Organs; Oxidation; Oxygen; Pharmacology; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Physical Sciences; Physiological aspects; Pyruvates - pharmacology; Pyruvates - therapeutic use; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reagents; Research and Analysis Methods; Respiration; Senescence; Survival; Toxicity; Transcription factors; Tumors; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174271

Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells. We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model. AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib. These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC.