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

in Materials today. Bio by Dan Yin, Xuan Wu, Xu Chen, Jian-Li Chen, Xinyue Xia, Jianfang Wang, Xiuping Chen, Xiao-Ming Zhu

TLDR

  • Combining a protein killer called carfilzomib with oxygen-generated nanoparticles may be an effective way to treat solid tumors.

Abstract

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) nanoparticles for effective combination therapy targeting the interplay between calcium overload and oxidative stress. Low-dose CaOsynergistically 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 CaOcomplement 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 CaOsimultaneously to the tumor, and results in a superior antitumor effect in U-87 MG tumor-bearing mice compared with monotherapy. Taken together, CaOholds 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.

Overview

  • The study focuses on improving the efficacy of proteasome inhibitors by combining them with calcium peroxide (CaO) nanoparticles for treating solid tumors.
  • The researchers use liposomes to encapsulate the proteasome inhibitor carfilzomib (CFZ) and CaO nanoparticles for effective combination therapy.
  • The primary objective of the study is to explore the potential of CaO in enhancing the anticancer effect of CFZ in human glioblastoma cells and in treating solid tumors.

Comparative Analysis & Findings

  • The study demonstrates that low-dose CaO synergistically enhances the anticancer effect of CFZ in human glioblastoma U-87 MG cells.
  • The combination of CFZ and CaO induces reactive oxygen species (ROS) generation, glutathione depletion, and endoplasmic reticulum (ER) stress, leading to calcium overload and mitochondrial dysfunction.
  • The liposome-based codelivery system shows a superior antitumor effect in U-87 MG tumor-bearing mice compared with monotherapy

Implications and Future Directions

  • The study suggests that CaO has great potential to sensitize proteasome inhibitors in the treatment of solid tumors.
  • The findings also present a new combination therapy strategy targeting the crosstalk between proteasome inhibitors and oxidative stress for future cancer therapy.
  • Future studies can explore the potential of this combination therapy strategy in treating other types of solid tumors and identifying the optimal doses of CFZ and CaO for effective treatment.
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