Acetylcholine receptor agonists effectively attenuated multiple program cell death pathways and improved left ventricular function in trastuzumab-induced cardiotoxicity in rats.

Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Chayodom Maneechote, Titikorn Chunchai, Busarin Arunsak, Sasiwan Kerdphoo, Siriporn C Chattipakorn, Nipon Chattipakorn

Life sciences 2023 Sep 15

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Cardiotoxicity is a seriously debilitating complication of trastuzumab (TRZ) therapy in patients with cancer as a consequence of overexpression of the human epidermal growth factor receptor 2. Although most TRZ-induced cardiotoxicity (TIC) cases are reversible, some patients experience chronic cardiac dysfunction, and these irreversible concepts may be associated with cardiomyocyte death. Acetylcholine receptor (AChR) activation has been shown to exert cardioprotection in several heart diseases, but the effects of AChR agonists against TIC have not been investigated. Forty adult male Wistar rats were randomized into 5 groups: (i) CON (0.9 % normal saline), (ii) TRZ (4 mg/kg/day), (iii) TRZ + α7nAChR agonist (PNU-282987: 3 mg/kg/day), (iv) TRZ + mAChR agonists (bethanechol: 12 mg/kg/day), and (v) TRZ + combined treatment (Combined PNU-282987 and bethanechol). The progression of TIC was driven by mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including by pyroptosis, ferroptosis, and apoptosis, which were significantly alleviated by α7nAChR and mAChR agonists. Interestingly, necroptosis was not associated with development of TIC. More importantly, the in vitro study validated the cytoprotective effects of AChR activation in TRZ-treated H9c2 cells, while not interfering with the anticancer properties of TRZ. All of these findings indicated that TRZ induced mitochondrial dysfunction, autophagic deficiency, and excessive myocyte death including pyroptosis, ferroptosis, and apoptosis, leading to impaired cardiac function. These pathological alterations were attenuated by α7nAChR and mAChR agonists. α7nAChR and mAChR agonists might be used as a future therapeutic target in the mitigation of TIC. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Chayodom Maneechote, Titikorn Chunchai, Busarin Arunsak, Sasiwan Kerdphoo, Siriporn C Chattipakorn, Nipon Chattipakorn. Acetylcholine receptor agonists effectively attenuated multiple program cell death pathways and improved left ventricular function in trastuzumab-induced cardiotoxicity in rats. Life sciences. 2023 Sep 15;329:121971