Periodic Reporting for period 1 - p38_InTh (Innovative therapeutic tools to ameliorate chemotherapy-induced cardiotoxicity)
Periodo di rendicontazione: 2018-12-01 al 2020-08-31
Personalized treatments together with earlier detection protocols have substantially improved survival rates for cancer patients. However, currently used chemotherapeutic drugs have serious side effects such as cardiotoxicity. Particularly, anthracyclines such as doxorubicin are known to induce cardiovascular toxicity in up to 30% of the patients. To mitigate cardiac damage, clinicians usually prescribe lower doses during a longer period, thus making the treatments less efficient and increase the risk of progressive cardiovascular complications, or sometimes use dexrazoxane as a cardioprotective agent. Therefore, there is an urgent medical need to develop new therapies, which reduce cardiac damage induced by anthracyclines, thus improving patients’ quality of life. Anthracyclines generate both DNA damage and oxidative stress, which activates p38α MAPK. Interestingly, the non-canonical, MAP2K-independent activation of p38α has been associated to cardiomyocyte death and heart failure, suggesting that specific targeting of the non-canonical p38α activation could be therapeutically useful for reducing the cardiotoxicity of chemotherapeutics. p38_InTh allowed us to advance in the structural and functional characterization of a new class of chemical inhibitors for p38α (NC-p38i). We have obtained data indicating that NC-p38i compounds do not interfere with the chemotherapeutic effect of anthracyclines in cancer cells. Moreover, we performed pre-clinical experiments, which support that NC-p38i compounds possess promising drug-like properties, including low cytotoxicity, high metabolic stability in human microsomes and a good pharmacokinetic profile in rats.