The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries

Abdel-Aziz, Amal Kamal; Mantawy, Eman M.; Said, Riham S.; Helwa, Reham

doi:10.1016/j.expneurol.2016.06.004

Cited by 44 publications

(12 citation statements)

References 60 publications

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“…In this regards, it has been shown that sunitinib-induced autophagic cell death contributed to its cardiotoxicity (Zhao et al, 2010 ). Impeded autophagic flux has been associated with sunitinib-induced chemobrain (chemotherapy-related cognitive impairment) (Abdel-Aziz et al, 2016 ). As our data strongly suggest a potential therapeutic synergy of a combination of sunitinib with Mcl-1/mTORC1 inhibitors such as sorafenib and rapalogues which are known to induce autophagy, this could be of crucial clinical relevance especially concerning the toxicity of such combination.…”

Section: Adverse Effects Of Sunitinib and Autophagymentioning

confidence: 99%

From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib

et al. 2017

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Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome.

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Section: Adverse Effects Of Sunitinib and Autophagymentioning

confidence: 99%

From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib

et al. 2017

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“…However, tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in mice via dysregulation of VEGF receptor signaling. [42].…”

Section: Chemobrainmentioning

confidence: 99%

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

Walczak¹,

Janowski²

2019

Neuropsychiatry

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Chemotherapy-induced cognitive impairment or chemobrain is a frequent consequence of cancer treatment with many psychiatric features. Ironically, the increasing efficacy of chemotherapy leaves growing number of patients alive with chemobrain. Therefore, there is an urgent need for strategies capable of returning cancer survivors back to their pre-morbid quality of life. Molecular mechanisms of chemobrain are largely unknown. Over the last decade there was a lot of emphasis in preclinical research on inflammatory consequences of chemotherapy and oxidative stress but so far none of these approaches were translated into clinical scenario. The co-administration of chemotherapy with protective agents was evaluated preclinically but it should be introduced with caution as potential interference was not yet studied and that could blunt therapeutic efficacy. Stem cell-based regenerative medicine approach has so far been exploited very sparsely in the context of chemobrain and the focus was on indirect mechanisms or neuronal replacement in the hippocampus. However, there is evidence for widespread white matter abnormalities in patients with chemobrain. This is quite logical considering life-long proliferation and turnover of glial cells, which makes them vulnerable to chemotherapeutic agents. Feasibility of glia replacement has been established in mice with global dysmyelination where profound therapeutic effect has been observed but only in case of global cell engraftment (across the entire brain). While global glia replacement has been achieved in mice translation to clinical setting might be challenging due to much larger brain size. Therefore, a lot of attention should be directed towards the route of administration to accomplish widespread cell delivery. Techniques facilitating that broad cell distribution including intra-arterial and intrathecal methods should be considered as very compelling options. Summarizing, chemobrain is a rapidly growing medical problem and global glia replacement should be considered as worthwhile therapeutic strategy.

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“…100,101 A subsequent mouse study revealed that sunitinib impaired spatial cognition as evidenced in Morris water maze, T-maze, and a passive avoidance task, and adversely affected cortical and hippocampal neurons. 102 In a study evaluating the effect of antiangiogenic targeted therapy (primarily TK inhibitors), more than 30% of patients treated with such drugs developed cognitive decline. 103 …”

Section: Risk Factors For Crcimentioning

confidence: 99%

Cognitive Effects of Chemotherapy and Cancer-Related Treatments in Older Adults

Vega

Dumas

Newhouse

2017

The American Journal of Geriatric Psychiatry

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Advances in cancer treatment are producing a growing number of cancer survivors; therefore, issues surrounding quality of life during and following cancer treatment have become increasingly important. Chemotherapy-related cognitive impairment (CRCI) is a problem that is commonly reported following the administration of chemotherapy treatment in patients with cancer. Research suggests that CRCI can persist for months to years after completing treatment, which has implications for the trajectory of normal and pathologic cognitive aging for the growing number of long-term cancer survivors. These problems are particularly relevant for older individuals given that cancer is largely a disease of older age, and the number of patients with cancer who are age 65 years or older will increase dramatically over the coming decades. This review will briefly summarize empirical findings related to CRCI, discuss CRCI in older patients with cancer, potential causative hypotheses, and provide a canonical patient case to illustrate how CRCI presents clinically. Finally, potential intervention strategies for CRCI will be highlighted and issues to consider when evaluating older patients with a history of cancer will be discussed.

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The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries

Cited by 44 publications

References 60 publications

From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib

From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

Cognitive Effects of Chemotherapy and Cancer-Related Treatments in Older Adults

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