Abstract
Trastuzumab (TZM) is useful in the clinical management of HER2-positive metastatic breast, gastric, and colorectal carcinoma but has been limited by its off-target cardiotoxicity. This study investigates the therapeutic potentials of 0.25 mg/kg/day amlodipine, 0.035 mg/kg/day lisinopril, 5 mg/kg/day valsartan, and their fixed-dose combinations in TZM-intoxicated Wistar rats that were randomly allotted into 10 groups of 6 rats for each group. Group I rats were treated with 10 ml/kg/day sterile water orally and 1 ml/kg/day sterile water intraperitoneally; Groups II, III, and IV rats were orally gavaged with 5 mg/kg/day valsartan and 1 ml/kg/day sterile water intraperitoneally, 0.25 mg/kg/day amlodipine and 1 ml/kg/day sterile water via the intraperitoneal route, 0.035 mg/kg/day lisinopril and 1 ml/kg/day sterile water administered intraperitoneally, respectively. Group V rats were orally treated with 10 ml/kg/day of sterile water prior to intraperitoneal administration of 2.25 mg/kg/day of TZM. Groups VI–VIII rats were equally pretreated with 5 mg/kg/day valsartan, 0.25 mg/kg/day amlodipine, and 0.035 mg/kg/day lisinopril before intraperitoneal 2.25 mg/kg/day TZM treatment, respectively; Groups IX and X rats were orally pretreated with the fixed-dose combinations of 0.25 mg/kg/day amlodipine +0.035 mg/kg/day lisinopril and 5 mg/kg/day valsartan +0.035 mg/kg/day lisinopril, respectively, before TZM treatment. Cardiac injury and tissue oxidative stress markers, complete lipids profile, histopathological, and immunohistochemical assays were the evaluating endpoints. Results showed that repeated TZM treatments caused profound increases in the serum TG and VLDL-c levels, serum cTnI and LDH levels, and cardiac tissue caspase-3 and -9 levels but decreased BCL-2 expression. TZM also profoundly attenuated CAT, SOD, GST and GPx activities, and increased MDA levels in the treated tissues. In addition, TZM cardiotoxicity was characterized by marked vascular and cardiomyocyte congestion and coronary artery microthrombi formation. However, the altered biochemical, histopathological, and immunohistochemical changes were reversed with amlodipine, lisinopril, valsartan, and fixed-dose combinations, although fixed-dose valsartan/lisinopril combination was further associated with hyperlipidemia and increased AI and CRI values and coronary artery cartilaginous metaplasia. Thus, the promising therapeutic potentials of amlodipine, lisinopril, valsartan and their fixed-dose combinations in the management of TZM cardiotoxicity, majorly mediated via antiapoptotic and oxidative stress inhibition mechanisms were unveiled through this study.
Highlights
Cancer remains a major public health issue all around the world and is presently considered the second leading cause of death globally, accounting for an estimated 9.6 million deaths or one in six deaths with approximately 70% of these deaths occurring in low- and middle-income countries in the year 2018 (World Health Organization, 2018; Siegel et al, 2020)
® ® ® Herzuma, Ogivri, etc.) is a recombinant DNA-derived, humanized mouse IgG kappa monoclonal antibody targeted against the subdomain IV of the extracellular region of human epidermal growth factor receptor 2 (HER2)-expressed tumors (Poon et al, 2013; Porta et al, 2015; Fang et al, 2020).TZM is one of the HER2-targeted monoclonal antibodies approved for the clinical management of HER2 overexpressing metastatic solid tumors such as breast and gastric cancers (Lameire, 2014; Porta et al, 2015), gastroesophageal adenocarcinoma (Blackwell et al, 2010; Poon et al, 2013), and salivary duct carcinoma (Gibo et al, 2019)
Oral pretreatments with ADP and LSP to normal rats resulted in significant (p < 0.001) reductions in % Δbwt. when compared to Group I values
Summary
Cancer remains a major public health issue all around the world and is presently considered the second leading cause of death globally, accounting for an estimated 9.6 million deaths or one in six deaths with approximately 70% of these deaths occurring in low- and middle-income countries in the year 2018 (World Health Organization, 2018; Siegel et al, 2020). This figure has been predicted to increase to 19 million sufferers by the year 2030 (Corremans et al, 2019). The wide clinical application of TZM has profoundly improved the survival and recovery chances of patients with advanced HER2-positive breast and gastric cancers but has reportedly been limited by its cumulative and reversible off-target organ toxicities, most common of which is cardiotoxicity (Hidalgo et al, 2013; Onitilo et al, 2014; Mohan et al, 2018)
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