Sunitinib-mediated cytotoxicity is mostly reversible. Sunitinib impinges on cellular energy homeostasis, via disrupting the mitochondrial function through the inhibition of AMPK signaling. This induces mPTP opening, ΔΨ dissipation, swollen mitochondria, disrupted cristae, and a massive decrease of intracellular ATP, but low cytochrome c release and apoptosis. Sunitinib has been suggested to be also able to increase the autophagic flux and to inhibit ribosomal protein S6 kinase (RSK), thus activating Bad. By inhibiting VEGFR and PDGFR, sunitinib impairs angiogenesis and reduces adaptation to cardiac stress.