The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries.
Chemobrain refers to a cluster of cognitive deficits which affects almost 4-75% of chemotherapy-treated cancer patients. Sunitinib, an FDA-approved multityrosine kinase inhibitor, is currently used in treating different types of tumors. Despite being regarded as targeted therapy which blunts sustained angiogenesis in cancer milieu through inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) signaling, the latter has a cardinal role in cognition. Recent clinical reports warned that sunitinib adversely affected memory processing in cancer patients. Nevertheless, the underlying mechanisms have not been investigated yet. Hence, we explored the impact of a clinically relevant dose of sunitinib on memory processing in vivo and questioned the implication of VEGFR2 signaling, autophagy and apoptosis. Strikingly, sunitinib preferentially impaired spatial cognition as evidenced in Morris water maze, T-maze and passive avoidance task. Consistently, sunitinib degenerated cortical and hippocampal neurons as assessed by histopathological examination and toluidine blue staining. Ultrastructural examination also depicted chromatin condensation, mitochondrial damage and accumulated autophagosomes. Digging deeper, central VEGF/VEGFR2/mTOR signaling was robustly suppressed. Besides, sunitinib boosted cortical and hippocampal p53 and executioner caspase-3 and decreased nuclear factor kappa B and Bcl-2 levels promoting apoptotic cell death. It also profoundly impeded neuronal autophagic flux as shown by decreased beclin-1 and Atg5 and increased p62/SQTSM1 levels. To our knowledge, this is the first study to provide molecular insights into sunitinib-induced chemofog where impeded VEGFR2 signaling and autophagic and hyperactivated apoptotic machineries act in neurodegenerative concert. Importantly, our findings shed light on potential therapeutic strategies to be exploited in the management of sunitinib-induced chemobrain.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: AmalAbdel-Aziz@pharma.asu.edu.eg.
Amal Kamal
AK
Abdel-Aziz
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Eman M
EM
Mantawy
National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt.
Riham Soliman
RS
Said
Zoology Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
Reham
R
Helwa
D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001362:Avoidance Learning / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced; D065808:Prepulse Inhibition / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D012333:RNA, Messenger; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib
Apoptosis; Autophagy; Cognition; Sunitinib; VEGF