High-throughput screening identified mitoxantrone to induce death of hepatocellular carcinoma cells with autophagy involvement |
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| Affiliation: | 1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China;2. Department of Neuroscience, University of Uppsala, Uppsala, Sweden;3. Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden;4. School of Clinical Medicine, Dali University, Yunnan, China;5. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden;1. Department of Physics and Biophysics, University of Warmia and Mazury in Olsztyn, Oczapowskiego 4, 10-719 Olsztyn, Poland;2. Division of Food Science, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland;1. Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China;2. Department of Rehabilitation Medicine, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China;3. Department of Medical Genetics and Cell Biology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, China;1. College of Animal Veterinary Medicine, Yunnan Agricultural University, Kunming 650201, Yunnan, China;2. Center for Animal Disease Control and Prevention, Chuxiong 675000, Yunnan, China;3. First Affiliated Hospital of China Medical University, Shenyang 110001, China;4. School of Basic Medicine, Dali University, Dali 671003, Yunnan, China;5. Department of Oncology-Pathology, Karolinska Institute, 17176 Stockholm, Sweden;6. School of Clinical Medicine, Dali University, Dali 671003, Yunnan, China;1. State Key Laboratory of Cotton Biology, Key Laboratory of Plant Stress Biology, School of Life Sciences, Henan University, 85 Minglun Street, Kaifeng, 475001, China;2. College of Life and Environment Sciences, Shanghai Normal University, Guilin Road 100, Shanghai, 200234, China;3. Department of Molecular Biology, University of Geneva, Geneva, 1211, Switzerland;4. Department of Plant Biology, University of Geneva, Geneva, 1211, Switzerland;1. Department of Periodontics, Shenyang Stomatological hospital, Shenyang, Liaoning, People’s Republic of China;2. Department of Oral Surgery, Shenyang Stomatological hospital, Shenyang, Liaoning, People’s Republic of China;3. Department of Pediatric Intensive Care Unit, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China |
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| Abstract: | The use of highly efficient high-throughput screening (HTS) platform has recently gained more attention as a plausible approach to identify de novo therapeutic application potential of conventional anti-tumor drugs for cancer treatments. In this study, we used hepatocellular carcinoma (HCC) cells as models to identify cytotoxic compounds by HTS. To identify cytotoxic compounds for potential HCC treatments, 3271 compounds from three well established small molecule libraries were screened against HCC cell lines. Thirty-two small molecules were identified from the primary screen to induce cell death. Particularly, mitoxantrone (MTX), which is an established antineoplastic drug, significantly and specifically inhibited the growth and proliferation of HCC cells in vitro. Mechanistic studies of LC3-II, p62 and phosphorylation of p70S6K in HepG2 cells revealed that MTX treatment induced mTOR-dependent autophagy activation, which was further confirmed by the autophagic flux assay using lysosomal inhibitor chloroquine (CQ). In the combined treatment of MTX and CQ, where autophagy was inhibited by CQ, the elevations of cleaved Caspase-3 and PARP were observed, indicating the enhanced apoptosis in HepG2 cells. Taken together, we hypothesize that MTX-induced autophagy plays an pro-survival role in HCC treatment. Combined treatment with autophagy inhibitor may combat the chemo-resistance of HCC to MTX treatment and therefore deserves future clinical investment. |
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| Keywords: | Hepatocellular carcinoma Small molecule screen Mitoxantrone (MTX) Cell death Autophagy |
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