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Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca(2+) Overload

Authors
Lee, AR | Seo, MJ | Kim, J | Lee, DM | Kim, IY | Yoon, MJ | Hoon, H  | Choi, KS
Citation
International journal of molecular sciences, 20(24). : 6112-6112, 2019
Journal Title
International journal of molecular sciences
ISSN
1422-0067
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 Ca(2+) 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.
Keywords
MeSH

DOI
10.3390/ijms20246112
PMID
31817163
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Ajou Authors
최, 경숙  |  허, 훈
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