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Pyrrolidine dithiocarbamate reverses Bcl-xL-mediated apoptotic resistance to doxorubicin by inducing paraptosis

Authors
Park, SS; Lee, DM; Lim, JH; Lee, D; Park, SJ; Kim, HM; Sohn, S; Yoon, G; Eom, YW; Jeong, SY; Choi, EK; Choi, KS
Citation
Carcinogenesis, 39(3):458-470, 2018
Journal Title
Carcinogenesis
ISSN
0143-33341460-2180
Abstract
Elevated Bcl-xL expression in cancer cells contributes to doxorubicin (DOX) resistance, leading to failure in chemotherapy. In addition, the clinical use of high-dose doxorubicin (DOX) in cancer therapy has been limited by issues with cardiotoxicity and hepatotoxicity. Here, we show that co-treatment with pyrrolidine dithiocarbamate (PDTC) attenuates DOX-induced apoptosis in Chang-L liver cells and human hepatocytes, but overcomes DOX resistance in Bcl-xL-overexpressing Chang-L cells and several hepatocellular carcinoma (HCC) cell lines with high Bcl-xL expression. Additionally, combined treatment with DOX and PDTC markedly retarded tumor growth in a Huh-7 HCC cell xenograft tumor model, compared to either mono-treatment. These results suggest that DOX/PDTC co-treatment may provide a safe and effective therapeutic strategy against malignant hepatoma cells with Bcl-xL-mediated apoptotic defects. We also found that induction of paraptosis, a cell death mode that is accompanied by dilation of the endoplasmic reticulum and mitochondria, is involved in this anti-cancer effect of DOX/PDTC. The intracellular glutathione levels were reduced in Bcl-xL-overexpressing Chang-L cells treated with DOX/PDTC, and DOX/PDTC-induced paraptosis was effectively blocked by pretreatment with thiol-antioxidants, but not by non-thiol antioxidants. Collectively, our results suggest that disruption of thiol homeostasis may critically contribute to DOX/PDTC-induced paraptosis in Bcl-xL-overexpressing cells.
MeSH terms
AnimalsAntineoplastic Agents/pharmacology*Apoptosis/drug effectsCarcinoma, Hepatocellular/drug therapyCarcinoma, Hepatocellular/geneticsCell Line, TumorDoxorubicin/pharmacology*Drug Resistance, Neoplasm/drug effects*Drug Resistance, Neoplasm/geneticsHumansLiver Neoplasms/drug therapyLiver Neoplasms/geneticsMaleMiceMice, Inbred BALB CMice, NudePyrrolidines/pharmacology*Thiocarbamates/pharmacology*Xenograft Model Antitumor Assaysbcl-X Protein/genetics*
DOI
10.1093/carcin/bgy003
PMID
29329420
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
손, 성향윤, 계순최, 경숙
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