New target for chemotherapy-induced cardiac dysfunction

Introduction Cardio-oncology is a field aiming to improve cardiovascular outcomes of patients going through cancers and chemotherapies. Circulating Dipeptidyl Peptidase 3 (cDPP3) is a novel plasmatic biomarker for outcome in critically ill patients and has a negative inotropic effect in in vivo experiments. Intracellularly, DPP3 mainly protects cells against oxidative stress, and is upregulated in many types of cancer, its tumor expression upregulation correlating with poorer patient outcome. DPP3 silencing in colorectal cancer or esophageal cancer cells prevents tumor growth and migration in vitro and in vivo. Aim The aim is to elucidate if DPP3 is released by cancer and cardiac cells under chemotherapy treatment or not, and to determine the interplay between cDPP3 concentrations and heart function during doxorubicin-induced cardiotoxicity. Methods Murine cancer cell lines ID8 (ovarian), PY8119 (breast) and 4T1 (breast), human cardiomyocytes (AC16) and human cancer cells MB-231 (breast) were submitted to doxorubicin (dox, 1µM) treatment and DPP3 activity was assessed in the culture media (secretome). Wild-type (WT) and knock-out (KO)-DPP3 mice were injected with dox (cumulative dose of 24 mg/kg, intraperitoneally, 6 days) while heart function and cDPP3 were quantified weekly for three weeks. Results DPP3 was found selevated in the secretome of Dox-treated cells compared to their control, indicating that stressing the cells chemically lead to a release of DPP3. Dox-treated secretome of ID8 lead to a significant reduction of AC16 cell-viability (2-fold, p <0.05). In vivo, KO-DPP3 dox-treated mice had a significant decrease (-13%, p<0.05) in fractional shortening (FS) at week one, more severe than WT-dox-treated mice (-6%, p<0.05). FS was restored to almost baseline-levels at week three in KO-mice, but no improvement of heart function was seen in WT-mice at week three (p<0.05). Furthermore, KO-dox-treated mice showed less mortality than WT-dox-treated mice (p<0.05). Interestingly, cDPP3 activity increased in WT-dox-treated mice at week one (220 U/L vs 130 U/L in control, p<0.05), reaching its peak at two weeks, and stayed elevated until sacrifice at week three. As expected, no cDPP3 activity was detected in KO-DPP3 mice. Conclusion DPP3 is released by cancerous and cardiovascular cells. cDPP3 activity is elevated in WT-dox-treated mice DPP3 deletion prevented from cardiac dysfunction induced by dox. These results suggest a potential role of DPP3 in chemotherapy-associated cardiac dysfunction.