Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis

Co-treatment with a drug that disrupts protein breakdown and another that activates tumor suppressor proteins can induce cancer cell death. Kyeong Sook Choi and colleagues from Ajou University School of Medicine in Suwon, South Korea, studied various solid tumor cell lines that did not have working versions of the p53 tumor suppressor and were resistant to bortezomib, a drug that blocks the protein-degrading complex known as the proteasome. The researchers treated the cells with nutlin-3 – a drug that normally activates p53 but, in its absence, can induce the mitochondrial unfolded protein response – and saw minimal effects on cell viability. But administering bortezomib and nutlin-3 together led to the induction of a form of cell death known as paraptosis in which empty spaces form inside the cell due to the dilation of the endoplasmic reticulum and mitochondria.