Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies

Junho Lee, Jin Su Kim and Yangjin Kim

PLOS Computational Biology, 2021, vol. 17, issue 10, 1-28

Abstract: Acute administration of trastuzumab (TZB) may induce various forms of cognitive impairment. These cancer-related cognitive changes (CRCC) are regulated by an adverse biological process involving cancer stem cells (CSCs) and IL-6. Recent studies have reported that atorvastatin (ATV) may change the dynamic of cognitive impairment in a combination (TZB+ATV) therapy. In this study, we investigate the mutual interactions between cancer stem cells and the tumor cells that facilitate cognitive impairment during long term TZB therapy by developing a mathematical model that involves IL-6 and the key apoptotic regulation. These include the densities of tumor cells and CSCs, and the concentrations of intracellular signaling molecules (NFκB, Bcl-2, BAX). We apply the mathematical model to a single or combination (ATV+TZB) therapy used in the experiments to demonstrate that the CSCs can enhance CRCC by secreting IL-6 and ATV may interfere the whole regulation. We show that the model can both reproduce the major experimental observation on onset and prevention of CRCC, and suggest several important predictions to guide future experiments with the goal of the development of new anti-tumor and anti-CRCC strategies. Moreover, using this model, we investigate the fundamental mechanism of onset of cognitive impairment in TZB-treated patients and the impact of alternating therapies on the anti-tumor efficacy and intracellular response to different treatment schedules.Author summary: A conventional drug, trastuzumab (TZB), was shown to be an effective weapon in killing cancer cells in brain. However, long term treatment of TZB increases the proportion of cancer stem cells (CSCs) in the tumour microenvironment (TME) and induces up-regulation of pro-tumoral molecules such as IL-6 in TME. These cancer cells then become more resistant to this chemotherapy through the IL-mediated up-regulation of NFκB and CSCs. More importantly, these changes in TME result in a serious side effect, cognitive impairment called cancer-related cognitive changes (CRCC). The detailed mechanism of CRCC is still poorly understood. However, cancer patients with chemotherapy-induced cognitive impairment can have long-term or delayed mental changes. In this study, we investigated the fundamental mechanism of CRCC in cancer patients based on experiments and a mathematical model that describes how tumor cells interact with CSCs in response to chemo drugs. In particular, we investigate how TZB-induced CSCs with modified IL-6 landscapes shape the cognitive functions in cancer patients. We showed that the combination treatment with another drug, atorvastatin (ATV), can abrogate the TZB-induced CRCC and enhance the survival probability of cancer patients by synergistic anti-tumor effect. We demonstrate that the cognitive functions and survival rates in cancer patients depend on the apoptotic signaling pathways via the critical communication and IL-6 landscapes of stimulated CTCs.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1009457

DOI: 10.1371/journal.pcbi.1009457

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