Enhanced anticancer effect of carfilzomib by codelivery of calcium peroxide nanoparticles targeting endoplasmic reticulum stress.

Encouraged by the clinical success of proteasome inhibitors treating hematological malignancy, continuous efforts are being made to improve their efficacy and expand their applications to solid tumor therapy. In this study, liposomes were used to encapsulate the proteasome inhibitor carfilzomib (CFZ) and calcium peroxide (CaO(2)) nanoparticles for effective combination therapy targeting the interplay between calcium overload and oxidative stress. Low-dose CaO(2) synergistically enhances the anticancer effect of CFZ in the human glioblastoma U-87 MG cells. The reactive oxygen species (ROS) generation and glutathione depletion by low-dose CaO(2) complement CFZ-induced ubiquitinated protein accumulation further triggering endoplasmic reticulum (ER) stress leading to calcium overload and mitochondrial dysfunction. The liposome-based codelivery system is capable of transporting CFZ and CaO(2) simultaneously to the tumor, and results in a superior antitumor effect in U-87 MG tumor-bearing mice compared with monotherapy. Taken together, CaO(2) holds great potential to sensitize proteasome inhibitors in the treatment of solid tumors, and this work also presents a new combination therapy strategy targeting the crosstalk between proteasome inhibitors and oxidative stress for future cancer therapy.