Targeted disruption of mitochondria potently reverses multidrug resistance in cancer therapy

Br J Pharmacol. 2022 Jan 18. doi: 10.1111/bph.15801. Online ahead of print.

Abstract

Background and purpose: Multidrug resistance (MDR) is a major obstacle to the successful treatment of cancer. Ample evidence shows that ATP-binding cassette (ABC) transporters and high-energy states in cells are linked to cancer drug resistance. Our previous work reported an engineered therapeutic protein named PAK, which selectively inhibited tumour progression by targeting mitochondria.

Experimental approach: We studied the effects of PAK on reversing drug resistance in MDR phenotypic cells and xenograft mouse models. Effects of PAK on the process of mitochondrial energy production, ABC transporter expression, and drugs enrichment were investigated in cancer cells. RNA-seq and co-immunoprecipitation were employed to analyse the mechanism of PAK on the redistribution of ABC transporters.

Key results: PAK promoted the enrichment of drugs in MDR cancer cells, thus enhancing the sensitivity of cancer cells to chemotherapy. Furthermore, PAK was colocalized in the mitochondria and initiated mitochondrial injury by selectively inhibiting the mitochondrial complex V. Also, ABCB1 and ABCC1 were redistributed from the plasma membrane to the cytoplasm through the disruption of lipid rafts, which was attributed to the low energy state and decreased cholesterol levels.

Conclusions and implications: Our results revealed a previously unrecognized pattern of reversal of drug resistance and have suggested mitochondria as a clinically relevant target for the treatment of MDR malignant tumours.

Keywords: ABC transporters; cholesterol metabolism; lipid rafts; mitochondria; multidrug resistance; therapeutic protein.