From vulnerability to resilience: molecular mechanisms of cancer therapy-induced cardiotoxicity
From vulnerability to resilience: molecular mechanisms of cancer therapy-induced cardiotoxicity
Cancer treatment has become remarkably effective, but saving lives from cancer can come with a hidden cost to the heart. Anthracyclines, a family of widely used cancer drugs with doxorubicin as their most prominent member, can cause serious heart damage in some patients, sometimes years after treatment ends. Yet two patients receiving identical treatment can have completely different outcomes: one develops heart failure, while the other remains perfectly healthy. Why?
This thesis of Itamar Braga Dias set out to answer that question. Using stem cell technology, we built living, beating cardiac tissue in the laboratory and exposed it to drug concentrations mimicking actual patient treatment. We found that doxorubicin drives heart cells into cellular senescence, a permanent standstill where cells stop functioning normally but do not die, closely mirroring natural cardiac aging. Attempts to remove these senescent cells with targeted drugs backfired, worsening heart function.
A key discovery came from comparing heart cells of patients who suffered heart failure with those who tolerated far higher doses without problems. Vulnerable patients carried higher levels of damage in the DNA of their mitochondria, the cell's energy factories, before treatment began. This genetic wear-and-tear, combined with weaker antioxidant defenses, left their hearts with insufficient reserve to absorb the stress of chemotherapy. Vulnerability is not simply about dose; it is written into the cells from the start.
Finally, a newer drug, ribociclib, was found to damage the heart through an entirely different mechanism, showing that cardiac protection during cancer treatment must be tailored to the individual.