Comparative Neurotoxic Effects of Doxorubicin and Sunitinib: An In Vitro Study on Human Dopaminergic Neuronal Cells

Chemotherapy-induced cognitive impairment, commonly referred to as chemobrain, is a well-documented adverse outcome of anticancer treatments. While the neurotoxicity of doxorubicin (DOX) has been extensively studied, targeted therapies such as sunitinib (SUN) remain largely unexplored concerning this outcome. This study aimed to compare the neurotoxic effects of DOX and SUN in dopaminergic neuronal cells and to explore the involvement of oxidative stress and autophagy as potential mechanisms underlying their cytotoxicity. Human neuronal SH-SY5Y cells were differentiated into a dopaminergic phenotype and exposed to clinically relevant concentrations of DOX (0.1-10 µM) and SUN (1-10 µM) for 24 or 48 h. To investigate the involvement of oxidative stress in their cytotoxicity, redox modulators [N-acetylcysteine (NAC); dimethyl fumarate (DMF); sulforaphane (SFN); and cheirolin (CH)] were tested alongside DOX and SUN for their potential protective effects. The role of autophagy in SUN-induced toxicity was assessed using 3-methyladenine (3-MA; an early-stage inhibitor); chloroquine (CH; a late-stage inhibitor); and rapamycin (RAP; an autophagy inducer). Additionally, LC3-I and LC3-II expression levels were determined. Both DOX and SUN exhibited time- and concentration-dependent cytotoxicity and induced mitochondrial membrane depolarization. NAC conferred partial protection against SUN toxicity but enhanced DOX's cytotoxicity at the lowest concentration tested. DMF and SFN had dual effects, depending on the drug's concentration, while CH exhibited a consistent protective effect towards the cytotoxicity induced by both drugs. Regarding autophagy, 3-MA partially protected against SUN-induced toxicity, whereas CLQ and RAP exacerbated it. LC3-II levels were increased in some conditions, suggesting that SUN-induced toxicity involves autophagy. This study shows that SUN, though less studied in chemobrain, has a cytotoxic profile similar to DOX, which is a known contributor to chemobrain, in SH-SY5Y cells. These findings highlight the need for further research on neuroprotective strategies targeting oxidative stress and autophagy to reduce chemobrain in cancer patients and survivors.