Chemobrain: An accelerated aging process linking adenosine A2A receptor signaling in cancer survivors

Abstract

Chemotherapy has a significant positive impact in cancer treatment outcomes, reducing recurrence and mortality. However, many cancer surviving children and adults suffer from aberrant chemotherapy neurotoxic effects on learning, memory, attention, executive functioning, and processing speed. This chemotherapy-induced cognitive impairment (CICI) is referred to as "chemobrain" or "chemofog". While the underlying mechanisms mediating CICI are still unclear, there is strong evidence that chemotherapy accelerates the biological aging process, manifesting as effects which include telomere shortening, epigenetic dysregulation, oxidative stress, mitochondrial defects, impaired neurogenesis, and neuroinflammation, all of which are known to contribute to increased anxiety and neurocognitive decline. Despite the increased prevalence of CICI, there exists a lack of mechanistic understanding by which chemotherapy detrimentally affects cognition in cancer survivors. Moreover, there are no approved therapeutic interventions for this condition. To address this gap in knowledge, this review attempts to identify how adenosine signaling, particularly through the adenosine A_2A receptor, can be an essential tool to attenuate accelerated aging phenotypes. Importantly, the adenosine A_2A receptor uniquely stands at the crossroads of cancer treatment and improved cognition, given that it is widely known to control tumor induced immunosuppression in the tumor microenvironment, while also posited to be an essential regulator of cognition in neurodegenerative disease. Consequently, we propose that the adenosine A_2A receptor may provide a multifaceted therapeutic strategy to enhance anticancer activity, while combating chemotherapy induced cognitive deficits, both which are essential to provide novel therapeutic interventions against accelerated aging in cancer survivors.

Keywords: Adenosine A(2A) receptor; Aging; Cancer; Cancer survivors; Chemobrain; Chemotherapy-induced cognitive impairment.

Fig. 1

Potential cellular and molecular mechanisms mediating the convergence of chemotherapy-induced cognitive impairment and accelerated aging phenotypes. Chemotherapy induced cognitive impairments (CICI) can be experienced by cancer patients with varying genotoxic mechanisms of action, including antifolate anti-metabolites (methotrexate), platinum-based compounds (cisplatin), as well as anthracyclines (doxorubicin), amongst others. Notably, mounting evidence suggests that generally, chemotherapies target multiple cellular and molecular mechanisms that, when disrupted, are widely known to negatively affect hallmarks of cognitive function, such as reductions in the neurogenic potential of the hippocampus, deficient functional neuronal architecture of dendrites yielding stunted dendrite spine densities, and impaired oligodendrocyte progenitor development which hinders myelination capacity. Several lines of evidence suggest that oxidative stress generated by mitochondrial defects, as well as neuroinflammatory sequelae resulting from proinflammatory cytokine penetration of the brain parenchyma (stemming from chemotherapy induced weakening of the blood brain barrier), are candidate hypotheses that may explain how CICI develops. Interestingly, the phenotypes that typify CICI also share a commonality with cellular and molecular detriments observed in cancer-related accelerated aging and neurodegenerative-related accelerated aging. These shared common pathological mechanisms include mitochondrial oxidative stress, and an increased proinflammatory cytokine secretory response engaged by chemotherapy’s apoptotic and necrotic effect on malignancies. Similarly, CICI and neurodegeneration associated accelerated aging share impairments in neurogenesis, synaptic function, and myelination. One pathway that may elucidate the commonality between CICI, cancer-related accelerated aging, and neurodegenerative associated accelerated aging, is through inhibition of adenosine A_2AR signaling. Inhibition of A_2AR has been demonstrated to sensitize chemotherapy against malignancies as well as prevent tumor induced immune evasion in the tumor microenvironment. Importantly, increased adenosine A_2AR is implicated with cognitive deficits in Alzheimer’s disease. A_2AR inhibition is associated with in improved cognition in preclinical models of neurodegenerative disease, as well as preservation of neuronal architecture, neurogenesis, and cognitive function in a preclinical model of cisplatin induced CICI. Taken together, we propose that CICI may be classified as a form of accelerated aging, and that the adenosine A2AR could serve as a unique nexus that can provide therapeutic efficacy in cancer survivors and accelerated aging phenotypes.