Targeted disruption of mitochondria potently reverses multidrug resistance in cancer therapy

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.

Modulating p-AMPK/mTOR Pathway of Mitochondrial Dysfunction Caused by MTERF1 Abnormal Expression in Colorectal Cancer Cells

“…The inhibition of mTOR also increases the drug sensitivity of cancer cells [ 35 ]. Therefore, targeting AMPK/mTOR can effectively inhibit tumor formation and enhance chemotherapeutic sensitivity, and disruption of ATP level may be a more straightforward strategy to overcome drug resistance [ 36 ]. Intriguingly, we found that MTERF1 knockdown contributed to the decrease in ATP levels in CRC cells, thereby activating p-AMPK and then inhibiting p-mTOR and the downstream effector proteins of p-mTOR, p-P70S6K, and p-4E-BP1, indicating that MTERF1 regulates tumor cell proliferation by the AMPK/mTOR signaling axis.…”

Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis

“…[ 10–12 ] Recently, chemotherapy, gene therapy, and phototherapy that target cancer cell mitochondria have been widely explored toward overcoming cancer drug resistance. [ 13–19 ] However, due to the complex drug resistance mechanisms, unique tumor microenvironment (such as hypoxia or endogenous H 2 O 2 deficiency), or their own limitations in case of drug activity or phototoxicity, the current strategies to safely and effectively induce mitochondrial dysfunction in cancer cells are still far from satisfaction. [ 20–23 ] In short, there is an ongoing and urgent need for the development of innovative strategies aimed at effectively inducing mitochondrial dysfunction to surmount drug resistance in cancer.…”