Mechanisms of chemotherapy-induced behavioral toxicities

Abstract

While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

Chemotherapy-Induced Neurotoxicity: Evidence of a Protective Role of CC Homozygosis in the Interleukin-1β Gene-511 C>T Polymorphism

“…They also present a hematopoietic damage and a greater occurrence of peripheral neurological deficits. All these changes are induced by chemotherapy, as reported in the literature (Windebank and Grisold 2008;Vichaya et al 2015).…”

“…Hence, this preliminary observation suggests that IL-1b-511 SNP could be a marker of susceptibility to chemotherapy-induced neurotoxicity and a possible protective role of the CC homozygosis in the IL1b gene-511 C[T polymorphism could be suggested. Possible pathological mechanisms involved in peripheral neurotoxicity have been extensively observed with evidences showing specific direct toxic mechanisms related to each chemotherapeutic class (e.g., mitochondrial functional impairment, DNA duplication or transcription errors, neurotransmitter deregulation, oxidative stress, neurotrophic factors deregulation, microtubule-based axonal transport interruption, small fiber loss, hypothalamic-pituitary axis activation (Windebank and Grisold 2008;Argyriou et al 2012;Wang et al 2012;Cavaletti and Marmiroli 2015;Vichaya et al 2015;Wang et al 2015)). Some indirect mechanisms are responsible for the maintenance of neurotoxicity after drug discontinuation in 30-35 % of patients (Argyriou et al 2012.…”

“…Neurologic side effects of chemotherapy can be classified as peripheral neuropathy, cognitive impairment, fatigue and motivational deficits (Vichaya et al 2015).…”

“…The cognitive changes have been associated with corresponding alterations in the brain integrity, perfusion, or metabolism, generally reversible after years, (Inagaki et al 2007;Baudino et al 2012;Ganz et al 2013). Neurotoxicity effects can be acute or chronic after multiple exposures, in a small, although significant portion of patients, the effects could persist after treatment discontinuation (Argyriou et al 2012;Vichaya et al 2015;Wang et al 2015).…”

“…Many authors proposed that inflammatory cascade activation, pro-inflammatory cytokine up regulation, and neuro-immune pathways play an essential role in the initiation and progression of neurotoxicity (Wang et al 2012;Vichaya et al 2015;Wang et al 2015).…”