1. Loperamide overcomes the resistance of colon cancer cells to bortezomib by inducing CHOP-mediated paraptosis-like cell death.
- Author
-
Kim IY, Shim MJ, Lee DM, Lee AR, Kim MA, Yoon MJ, Kwon MR, Lee HI, Seo MJ, Choi YW, and Choi KS
- Subjects
- Antidiarrheals pharmacology, Apoptosis physiology, Cell Death drug effects, Cell Death physiology, Cyclophosphamide pharmacology, Dose-Response Relationship, Drug, Doxorubicin pharmacology, Drug Resistance, Neoplasm physiology, HCT116 Cells, HeLa Cells, Humans, Prednisone pharmacology, Proteasome Inhibitors pharmacology, Vincristine pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Bortezomib pharmacology, Colonic Neoplasms pathology, Drug Resistance, Neoplasm drug effects, Loperamide pharmacology
- Abstract
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 Ca
2+ 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., (Copyright © 2018 Elsevier Inc. All rights reserved.) more...- Published
- 2019
- Full Text
- View/download PDF