Azithromycin Targets Mitochondrial Dysfunction and ER Stress to Rescue Doxorubicin-Induced Cardiotoxicity: In Vivo and In Vitro Evidence

Abstract

Doxorubicin is one of the main drugs used for cancer patients. The major issue with it is that it causes serious heart problems during treatment. At present there is no safe option to protect the heart without making the drug less effective against tumors. We checked azithromycin for this purpose. AZM is a routine antibiotic and past studies show it can reduce inflammation, ROS and ER stress.

We used C57BL/6 mice and H9c2 heart cells. Four groups were made: Control, AZM only, DOX only, and DOX+AZM. DOX was given 20 mg/kg i.p. single dose. AZM was given 50 mg/kg/day orally for 14 days. On day 14 we did echocardiography. Histology, fibrosis, ROS, JC-1, apoptosis and ER stress proteins were also checked. Antitumor effect was tested in 4T1 breast tumor model. H9c2 cells got DOX 1 µM and AZM 10 µM for 24h.

In the DOX group, 3 out of 8 mice died within 14 days. Body weight dropped by 18%. EF was 42.3 ± 4.1% and FS was 21.1 ± 2.8%. Heart sections showed 18.7 ± 2.3% fibrosis. In cells, viability was only 47.7 ± 4.7%. ROS increased 4.6 fold. JC-1 ratio was 0.31 ± 0.05. Apoptosis reached 38.7 ± 3.9% with high caspase-3, p-PERK and CHOP.

With DOX+AZM, all mice survived. Weight loss was just 5%. EF was 65.2 ± 3.9% and FS was 34.7 ± 3.1%. Fibrosis reduced to 6.1 ± 1.4%. Cell viability improved to 81.4 ± 5.2%. ROS came down to 1.8 fold. JC-1 ratio was 1.92 ± 0.18. cell death was only 12.3 ± 2.1%. p-PERK and CHOP were also lower. Tumor size in DOX group was 412 ± 68 mm³ and in DOX+AZM it was 435 ± 71 mm³. The difference was not significant.

So AZM protects heart cells from DOX by controlling ROS, mitochondria and ER stress pathways. It also does not affect tumor killing. This makes Azitheromycin a useful option to reduce heart risk in patients getting doxorubicin.