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- Title
Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca2+ Overload.
- Authors
Lee, A Reum; Seo, Min Ji; Kim, Jin; Lee, Dong Min; Kim, In Young; Yoon, Mi Jin; Hoon, Hur; Choi, Kyeong Sook
- Abstract
The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, carfilzomib, and ixazomib, in many solid tumor cell lines by inducing paraptosis, which is accompanied by severe vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. We found that Ler potentiates Btz-mediated ER stress and ER dilation, possibly due to misfolded protein accumulation, in MDA-MB 435S cells. In addition, the combination of Btz and Ler triggers mitochondrial Ca2+ overload, critically contributing to mitochondrial dilation and subsequent paraptotic events, including mitochondrial membrane potential loss and ER dilation. Taken together, our results suggest that a combined regimen of PI and Ler may effectively kill cancer cells via structural and functional perturbations of the ER and mitochondria.
- Subjects
ENDOPLASMIC reticulum; CANCER cells; MANTLE cell lymphoma; PROTEASOME inhibitors; MEMBRANE potential; MITOCHONDRIAL membranes
- Publication
International Journal of Molecular Sciences, 2019, Vol 20, Issue 24, p6112
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms20246112