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High-throughput screening identified mitoxantrone to induce death of hepatocellular carcinoma cells with autophagy involvement
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanchang, Jiangxi, Peoples R China.
Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanchang, Jiangxi, Peoples R China.
Nanchang Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanchang, Jiangxi, Peoples R China.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Larhammar: Pharmacology.
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2020 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 521, no 1, p. 232-237Article in journal (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE , 2020. Vol. 521, no 1, p. 232-237
Keywords [en]
Hepatocellular carcinoma, Small molecule screen, Mitoxantrone (MTX), Cell death, Autophagy
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-403253DOI: 10.1016/j.bbrc.2019.10.114ISI: 000506412100036PubMedID: 31653348OAI: oai:DiVA.org:uu-403253DiVA, id: diva2:1388675
Available from: 2020-01-27 Created: 2020-01-27 Last updated: 2020-01-27Bibliographically approved

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Zhang, XiaoLi, Jin-Ping

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