Mitochondrial Dynamin-Related Protein Drp1: a New Player in Cardio-oncology

Abstract

Purpose of Review This study is aimed at reviewing the recent progress in Drp1 inhibition as a novel approach for reducing doxorubicin-induced cardiotoxicity and for improving cancer treatment. Recent Findings Anthracyclines (e.g. doxorubicin) are one of the most common and effective chemotherapeutic agents to treat a variety of cancers. However, the clinical usage of doxorubicin has been hampered by its severe cardiotoxic side effects leading to heart failure. Mitochondrial dysfunction is one of the major aetiologies of doxorubicin-induced cardiotoxicity. The morphology of mitochondria is highly dynamic, governed by two opposing processes known as fusion and fission, collectively known as mitochondrial dynamics. An imbalance in mitochondrial dynamics is often reported in tumourigenesis which can lead to adaptive and acquired resistance to chemotherapy. Drp1 is a key mitochondrial fission regulator, and emerging evidence has demonstrated that Drp1-mediated mitochondrial fission is upregulated in both cancer cells to their survival advantage and injured heart tissue in the setting of doxorubicin-induced cardiotoxicity. Summary Effective treatment to prevent and mitigate doxorubicin-induced cardiotoxicity is currently not available. Recent advances in cardio-oncology have highlighted that Drp1 inhibition holds great potential as a targeted mitochondrial therapy for doxorubicin-induced cardiotoxicity.

PI3K/Akt/FoxO Pathway Mediates Antagonistic Toxicity in HepG2 Cells Coexposed to Deoxynivalenol and Enniatins

“…Mitochondria are abundant in hepatocytes . Drugs can directly or indirectly destroy the structure or function of mitochondria, resulting in accumulation of ROS, imbalance of Ca 2+ homeostasis, disappearance of MMP, and changes in mitochondrial membrane permeability, which ultimately leads to severe hepatotoxic effects .…”

“…41 It has been reported that the Ca 2+ levels are closely related to the ROS concentration, as ROS can regulate intracellular Ca 2+ signaling via multiple channels. 42 ATP plays an important role as an essential source of energy in various biological processes within 44 Drugs can directly or indirectly destroy the structure or function of mitochondria, resulting in accumulation of ROS, imbalance of Ca 2+ homeostasis, disappearance of MMP, and changes in mitochondrial membrane permeability, which ultimately leads to severe hepatotoxic effects. 45 The decline in the MMP is a hallmark event in the early stages of apoptosis.…”

Mitochondria-associated endoplasmic reticulum membranes (MAMs): Possible therapeutic targets in heart failure

“…Drp1, mitochondrial fission regulator, is upregulated in damaged cardiac tissues induced by doxorubicin. A study showed that Drp1 inhibitor will be a promising pharmacological agent, which inhibits the excessive mitochondrial fission mediated by doxorubicin and ameliorates its cardiotoxicity ( 79 ). Drp1 deficiency in adult mouse hearts showed the pathophysiological consequences of progressive ventricular enlargement and functional decompensation, resulting in heart failure ( 80 ).…”