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Carcinogenesis. 2018 Mar 8;39(3):458-470. doi: 10.1093/carcin/bgy003.

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

Author information

1
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea.
2
Department of Biomedical Sciences, Ajou Graduate School, Suwon, Korea.
3
Asan Institute for Life Sciences, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
4
Genomic Instability Center, Ajou University School of Medicine, Suwon, Korea.
5
Department of Pharmacy, Ajou University, Suwon, Korea.
6
Department of Energy Systems Research, Ajou University, Suwon, Korea.
7
Department of Microbiology, Ajou University, Suwon, Korea.
8
Cell therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei University, Wonju, Korea.
9
Center for Advancing Cancer Therapeutics, Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

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.

PMID:
29329420
DOI:
10.1093/carcin/bgy003
[Indexed for MEDLINE]

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