Dysfunctional high-density lipoprotein particles are associated with cardiac alterations in cancer patients and tumor-bearing mice receiving doxorubicin.

Abstract

Cancer patients receiving doxorubicin (DOX) chemotherapy are at high risk of developing cardiac alterations, but the mechanisms remain elusive. Both breast cancer and DOX therapy are associated with dyslipidemia. We aimed to investigate whether changes in high-density lipoprotein (HDL) particles subclass distribution and functionalities are associated with DOX-induced cardiac alterations in breast cancer patients and tumor-bearing mice. HDL particles subclasses were assessed using the Lipoprint® system in breast cancer patients (n = 34) and tumor-bearing mice at baseline and after receiving DOX chemotherapy. HDL particles antioxidative properties were assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9c2 cells. In breast cancer patients, DOX therapy reduced intermediate HDL particles subclasses, an effect that positively correlated with cardiac alterations. In mice, breast cancer shifted HDL particles subclasses distribution from intermediate to large HDL particles while DOX therapy increased small HDL particles. Both breast cancer and DOX therapy were associated with reduced PON1 activity. The decrease in intermediate HDL particles correlated with poorer cardiac function and lower PON1 activity. Interestingly, HDL particles isolated from tumor-bearing mice or from mice receiving DOX failed to protect H9c2 cells against DOX-induced cytotoxicity compared to HDL particles of healthy mice. In our study, a shift in HDL particles subclasses and functionalities correlated with cardiac alterations in cancer patients and mice treated with DOX. Consequently, our data warrant further research to explore whether targeting HDL particles may represent a therapeutic strategy to limit DOX-induced cardiotoxicity in breast cancer patients.