Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity
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Date
2021-03-04
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Frontiers in Pharmacology
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, 0.035mg/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 VIāVIII 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 0.25mg/kg/day
amlodipine +0.035mg/kg/day lisinopril and 5mg/kg/day valsartan +0.035mg/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 TZMtreatments 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 managementofTZMcardiotoxicity, majorly mediated via antiapoptotic and oxidative
stress inhibition mechanisms were unveiled through this study