The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti-cancer effects of do
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REVIEW ARTICLE
The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti‑cancer effects of doxorubicin Zaid H. Maayah1 · Shingo Takahara1 · Jason R. B. Dyck1,2 Received: 12 May 2020 / Accepted: 12 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Doxorubicin (DOX) is a powerful broad-spectrum anti-neoplastic anthracycline antibiotic. However, DOX may cause a dosedependent cardiotoxicity that can eventually progress to congestive heart failure and death. Numerous molecular mechanisms have been implicated in the cardiotoxic effect of DOX including topoisomerase IIβ and generation of free radicals. However, targeting these pathways appears to be insufficient to mitigate the cardiotoxic effects of DOX and/or ultimately reduces the anti-tumor activity of DOX. Thus, there remains a crucial need to identify novel pharmacological targets that can alleviate the cardiotoxic effects of DOX without reducing its anti-tumor activity. Recent studies have suggested that the NucleotideBinding Domain-Like Receptor Protein 3 (NLRP3) inflammasome is implicated in tumor progression and the chemoresistance of cancer cells to DOX. Of interest, reducing NLRP3 inflammasome activity alleviates DOX-induced cardiotoxicity. Therefore, we postulate that strategies that target the NLRP3 inflammasome can help mitigate the cardiotoxic effects of DOX while maintaining and/or even enhancing its anti-cancer activity. Herein, we review the current knowledge about the potential implication of the NLRP3 inflammasome in the anti-cancer and cardiotoxic effects of DOX. Keywords Doxorubicin · Inflammasome · NLRP3 · Heart · Cancer
Introduction Doxorubicin (DOX), a powerful anthracycline antibiotic, has broad-spectrum anti-neoplastic activity and thus continues to be central in the treatment of several types of human neoplasms, including breast cancer (Minotti et al. 2004). However, DOX may cause a dose-dependent cardiotoxicity that can eventually progress to congestive heart failure and death (Chatterjee et al. 2010; Felker et al. 2000; Horenstein et al. 2000). Nevertheless, despite the fact that DOX can trigger cardiotoxicity in approximately 30–50% of breast cancer patients if given at higher doses (Meinardi et al. 2001; Perez et al. 2004), DOX is still one of the major components of a chemotherapeutic regimen for the treatment of breast cancer (Trudeau et al. 2005). Thus, identifying new strategies to * Jason R. B. Dyck [email protected] 1
Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
458 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2, Canada
2
reduce the cardiotoxic effect of DOX so as to continue to use this effective therapy to treat cancer would improve the quality of life for breast cancer patients. Numerous molecular mechanisms have been implicated in the cardiotoxic effect of DOX (Wenningmann et al. 2019), including the formation of the
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