Bortezomib (Btz), a proteasome inhibitor (PI), is effective in treating multiple myeloma and mantle cell lymphoma, but its anticancer effects are not satisfactory in solid tumors. In this study, we examined the possibility that the sensitivity to PIs can be enhanced by drug repositioning. We first show that lercanidipine (Ler), an antihypertensive agent, increases the cytotoxicity of various PIs including Btz, carfilzomib (Cfz), and ixazomib (Ixz) by inducing paraptosis-associated cell death, which is accompanied by severe dilation of mitochondria and the endoplasmic reticulum (ER) and in many solid tumor cell lines. We have found that mitochondrial Ca2+ overload induced by the combination of Btz and Ler is crucial for mitochondrial vauolation and subsequent mitochondrial membrane potential loss in MDA-MB 435S cells. In addition, Ler enhances Btz-mediated ER stress due to accumulation of misfolded proteins, contributing to ER vacuolization. Taken together, our results suggest that the combined regimen of PIs and Ler can effectively kill cancer cells through structural and functional disturbance in mitochondria and the ER.
