Cardiolipin nanodisks confer protection against doxorubicin-induced mitochondrial dysfunction

Area of Science:

• Biochemistry
• Pharmacology
• Cardiology

Background:

• Doxorubicin (DOX) is a vital chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity.
• The precise molecular mechanisms underlying DOX-induced cardiotoxicity remain incompletely understood.
• DOX is known to interact with cardiolipin (CL), a key mitochondrial phospholipid.

Purpose of the Study:

• To investigate whether DOX association with cardiolipin nanodisks (CL-ND) affects its anti-cancer activity and cardiotoxicity.
• To explore the role of CL interaction in DOX-induced mitochondrial dysfunction and cardiotoxicity.

Main Methods:

• DOX was associated with CL-ND, a nanoparticle composed of CL and an apolipoprotein scaffold.
• Cell viability and growth inhibition assays were performed on cancer cell lines (HepG2, MCF7) and H9C2 cardiomyocytes.
• Maximal oxygen consumption rates were measured in H9C2 cardiomyocytes treated with free DOX or DOX-CL-ND.

Main Results:

• DOX-CL-ND demonstrated comparable anti-cancer growth inhibition activity to free DOX in cancer cells.
• DOX-CL-ND induced significantly less cell death in H9C2 cardiomyocytes compared to free DOX.
• Free DOX markedly reduced oxygen consumption in cardiomyocytes, while DOX-CL-ND had minimal impact.

Conclusions:

• Association of DOX with CL-ND preserves its anti-cancer efficacy while reducing cardiotoxicity.
• DOX interaction with CL is implicated in DOX-induced mitochondrial dysfunction and cardiotoxicity.
• CL-ND serve as a valuable tool for studying the mechanisms of DOX cardiotoxicity and developing safer therapeutic strategies.