Loperamide overcomes the resistance of colon cancer cells to bortezomib by inducing CHOP-mediated paraptosis-like cell death

[Display omitted] Although the proteasome inhibitor (PI) bortezomib (Btz) is in current clinical use as a front-line treatment for multiple myeloma, its clinical efficacy in solid tumors has not been satisfactory. Here, we show that loperamide (Lop), an antidiarrheal drug, effectively sensitizes var...

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Published in:Biochemical pharmacology 2019-04, Vol.162, p.41-54
Main Authors: Kim, In Young, Shim, Min June, Lee, Dong Min, Lee, A. Reum, Kim, Mi Ae, Yoon, Mi Jin, Kwon, Mi Ri, Lee, Hae In, Seo, Min Ji, Choi, Yong Won, Choi, Kyeong Sook
Format: Article
Language:English
Subjects:
Antidiarrheals - pharmacology
Antineoplastic Agents - pharmacology
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis - drug effects
Apoptosis - physiology
Bortezomib
Bortezomib - pharmacology
Cell Death - drug effects
Cell Death - physiology
CHOP
Colonic Neoplasms - pathology
Cyclophosphamide - pharmacology
Dose-Response Relationship, Drug
Doxorubicin - pharmacology
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - physiology
ER stress
HCT116 Cells
HeLa Cells
Humans
Loperamide
Loperamide - pharmacology
Paraptosis-like cell death
Prednisone - pharmacology
Proteasome Inhibitors - pharmacology
Vincristine - pharmacology
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Summary:[Display omitted] Although the proteasome inhibitor (PI) bortezomib (Btz) is in current clinical use as a front-line treatment for multiple myeloma, its clinical efficacy in solid tumors has not been satisfactory. Here, we show that loperamide (Lop), an antidiarrheal drug, effectively sensitizes various colon cancer cells, but not normal epithelial cells, to PI-mediated cell death. We report that combined treatment with Btz and Lop induces paraptosis-like cell death accompanied by severe endoplasmic reticulum (ER)-derived vacuolation. Furthermore, Lop potentiates Btz-mediated ER stress and ER dilation due to misfolded protein accumulation and Ca2+ imbalance, leading to CHOP upregulation and subsequent paraptosis-like cell death. Taken together, our results show for the first time that a combined regimen of PI and Lop may provide an effective and safe therapeutic strategy against solid tumors, including colon cancer, by enhancing the sensitivity to PIs and reducing the side effects of such treatment.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2018.12.006