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.
Highlights
Proteasome inhibition is an established treatment strategy for patients with multiple myeloma (MM) [1]
Various mechanisms have been proposed as underlying proteasome inhibitor (PI) resistance in solid tumors, including upregulated activity and increased subunit expression of proteasomes, proteasome β5-subunit mutations, protective autophagy, apoptosis-mediated resistance due to alteration of the Mcl-1/Noxa balance, elevation of P-glycoprotein resulting in Cfz efflux, and KRAS mutation associated with reprogramming of metabolic pathways [6]
In an attempt to identify a sensitizer that can effectively overcome the resistance of cancer cells to proteasome inhibitors (PIs), we investigated whether the antihypertensive drug, lercanidipine (Ler), could sensitize cancer cells to bortezomib (Btz)
Summary
Proteasome inhibition is an established treatment strategy for patients with multiple myeloma (MM) [1]. Despite the success of PIs in treating hematological malignancies, including MM, the PIs have shown limited clinical efficacy as mono-treatments for solid tumors [3,4]. Both innate and acquired resistance mechanisms can increasingly compromise the effectiveness of PI therapy [5]. We show that Ler and Btz synergistically kill breast cancer cells by inducing increased ER stress and intracellular Ca2+ imbalance In this process, mitochondrial Ca2+ accumulation critically contributes to mitochondrial dilation, mitochondrial membrane potential (MMP) loss, and subsequent ER dilation, resulting in the induction of paraptosis-associated cell death
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