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Open AccessArticle

Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca2+ Overload

by A Reum Lee 1,2,†, Min Ji Seo 1,2,†, Jin Kim 1,2, Dong Min Lee 1,2, In Young Kim 1, Mi Jin Yoon 1, Hur Hoon 2,3 and Kyeong Sook Choi 1,2,*
1
Department of Biochemistry and Molecular Biology, Ajou University, Suwon 16499, Korea
2
Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon 16499, Korea
3
Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(24), 6112; https://doi.org/10.3390/ijms20246112
Received: 20 October 2019 / Revised: 27 November 2019 / Accepted: 2 December 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
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. View Full-Text
Keywords: bortezomib; lercanidipine; ER stress; mitochondrial Ca2+ overload; paraptosis bortezomib; lercanidipine; ER stress; mitochondrial Ca2+ overload; paraptosis
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MDPI and ACS Style

Lee, A.R.; Seo, M.J.; Kim, J.; Lee, D.M.; Kim, I.Y.; Yoon, M.J.; Hoon, H.; Choi, K.S. Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca2+ Overload. Int. J. Mol. Sci. 2019, 20, 6112.

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