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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.

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


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.

[Indexed for MEDLINE]

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