BMP-7 Treatment Ameliorates PTEN-Akt Mediated Apoptosis and Adverse Cardiac Remodeling in Ponatinib-Induced Cardiotoxicity.

Background/

Objectives

Ponatinib (PON) is a potent anticancer drug widely used to treat chronic myeloid leukemia (CML). Although many cancer survivors benefit from such therapies, managing drug-induced side effects, especially cardiotoxicity, remains a major challenge. Despite its prevalence, the exact mechanisms underlying PON-induced cardiotoxicity have not been thoroughly investigated. Additionally, the potential of Bone Morphogenetic Protein 7 (BMP-7) to alleviate these cardiotoxic effects has yet to be explored.

Methods

To address these essential questions, we conducted a study using C57BL/6 mice. Mice were treated with PON (25 mg/kg cumulative dosage) or a combination of PON and BMP-7 (600 μg/kg), alongside a suitable control group. Heart function was assessed by echocardiography. Different techniques were performed to evaluate the apoptotic pathway. Histological staining was performed to investigate structural changes.

Results

PON treatment increased apoptotic cell death (increased expression of BAX and caspase-3) in the heart through the PTEN/Akt signaling pathway. Further, PON treatment led to increased cardiac hypertrophy, adverse remodeling, and reduced cardiac function. Importantly, BMP-7 markedly reduced PON-induced apoptosis (increased Bcl2 expression) and its downstream effects.

Conclusions

These results suggest that BMP-7 might inhibit PON-induced cardiotoxicity. Furthermore, our findings pave the way for future translational studies with BMP-7, which can demonstrate the therapeutic potential of BMP-7 in a clinical setting.