# (PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $482,478

## Abstract

Project Summary
This application addresses the Provocative Question 9: "What are the molecular and/or cellular mechanisms
that underlie the development of cancer therapy-induced severe adverse sequelae?" focusing on
Chemotherapy-induced cognitive impairments (CICI). CICI is now a recognized toxicity syndrome that includes
loss of executive function (confusion; memory issues), inability to multitask, and impaired intellectual
reasoning. While CICI caused by central nervous system (CNS)-directed therapies (such as radiation and
intrathecal chemotherapy) is readily understood, the mechanisms underlying a critical and shared toxicity of
chemotherapy that occurs after systemic cancer treatment with drugs that did not direct at the brain, are
unclear. The number of patients at risk for CICI from systemic therapy far exceeds the number of patients
exposed to CNS therapy, but little is known about the mechanisms mediating the effect of systemic therapy on
CICI, and there is no clear vision of how to prevent this condition. We have previously shown that generation
of reactive oxygen species (ROS) by cytotoxic chemotherapeutic drugs is an essential mediator of brain injury
even though the drug itself did not get into the brain. It is also imperative to note that anticancer medications,
designed specifically to target cancer cells with specialized features, such as the family of Bcl2 inhibitors, also
generate ROS. However, the effect of targeted therapy on CICI has never been addressed, and,
consequently, their mechanisms of action are entirely unknown. The goal of this proposal is to test the overall
hypothesis that therapy-induced ROS production in the target tissues leads to increased circulating TNFα
through extracellular vesicles (EVs)-mediated reactions, and this pro-inflammatory cytokine crosses the blood
brain barrier to elicit mitochondrial dysfunction and consequent neuronal injury leading to CICI. The following
specific aims are designed to test the ROS hypothesis, gain an understanding of the EVs-mediated
mechanisms, and test the proof-of-concept in an experimental cancer therapy setting using two prototype
chemotherapy agents (Doxorubicin and Venetoclax) that represent standard cytotoxic and experimental
targeted drugs in a lymphoma model. Aim 1 will investigate the fundamental role of TNFα in therapy-induced
neuronal injury to gain insights into mechanisms of CICI in the brain and demonstrate efficacy of chemotherapy
in the presence of redox-active antioxidants. Aim 2 will determine the mechanistic links between circulating
extracellular vesicles and therapy-induced CICI. Aim 3 will define the cell(s) of origin of TNFα produced during
chemotherapy that leads to cognitive impairment. These aims will be accomplished in vitro and in vivo using
state-of-the-art technologies, including magnetic resonance spectroscopy, redox proteomics, unique animal
models, and novel mitochondria targeting anti-oxidant, MnP, to ameliorate CICI without reducing the ...

## Key facts

- **NIH application ID:** 9982850
- **Project number:** 5R01CA217934-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** SUBBARAO BONDADA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,478
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982850

## Citation

> US National Institutes of Health, RePORTER application 9982850, (PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment (5R01CA217934-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9982850. Licensed CC0.

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