LAUSR

&NA; Although the proteasome inhibitor (PI) bortezomib (Btz) is in current clinical use as a front‐line treatment for multiple myeloma, its clinical efficacy in solid tumors has not been satisfactory. Here, we show that loperamide (Lop), an antidiarrheal drug, effectively sensitizes various colon cancer cells, but not normal epithelial cells, to PI‐mediated cell death. We report that combined treatment with Btz and Lop induces paraptosis‐like cell death accompanied by severe endoplasmic reticulum (ER)‐derived vacuolation. Furthermore, Lop potentiates Btz‐mediated ER stress and ER dilation due to misfolded protein accumulation and Ca2+ imbalance, leading to CHOP upregulation and subsequent paraptosis‐like cell death. Taken together, our results show for the first time that a combined regimen of PI and Lop may provide an effective and safe therapeutic strategy against solid tumors, including colon cancer, by enhancing the sensitivity to PIs and reducing the side effects of such treatment.