Morphine Deteriorates Cisplatin-Induced Cardiotoxicity in Rats and Induces Dose-Dependent Cisplatin Chemoresistance in MCF-7 Human Breast Cancer Cells

• Published in: Cardiovascular toxicology 2021-07, Vol.21 (7), p.553-562
• Main Authors: El-Sheikh, Azza A. K., Khired, Zenat
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics, Opioid - pharmacology; Analgesics, Opioid - toxicity; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Antineoplastic drugs; Antioxidants; Antitumor agents; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer cells; Cardiology; Cardiotoxicity; Caspase 3 - metabolism; Caspase-3; Catalase; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - toxicity; Creatine; Creatine kinase; Cytokines - metabolism; Cytotoxicity; Disease Models, Animal; Dosage and administration; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Neoplasm - drug effects; Enzymes; Female; Glutathione; Heart; Heart Diseases - chemically induced; Heart Diseases - metabolism; Heart Diseases - pathology; Heart Diseases - prevention & control; Humans; Inflammation; Inflammation Mediators - metabolism; Interleukin 6; Kinases; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Male; Malondialdehyde; Markers; MCF-7 Cells; Morphine; Morphine - pharmacology; Morphine - toxicity; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nitric oxide; Oxidants; Oxidative stress; Oxidative Stress - drug effects; Oxidizing agents; Peroxidation; Pharmacology/Toxicology; Rats; Rats, Wistar; Superoxide dismutase; Tissues; Toxicity testing
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-021-09646-1

Morphine (MOR) is a strong analgesic that is often used in treatment of severe pains during cancer treatment, and thus might be concomitantly used with anticancer drugs as cisplatin (CP). The aim of the current study was to investigate the mechanisms by which MOR can affect CP-induced cardiotoxicity and to explore effects of MOR on the cytotoxic efficacy of CP. MOR (10 mg/kg/day i.p.) was administered to rats for 10 days, with or without 7.5 mg/kg CP single i.p. dose at day 5 of the experiment. In addition, MOR and/or CP were administered to MCF-7 cells to test their cytotoxicity. Compared to control, CP caused cardiotoxic effects manifested by significant increase in serum enzymatic markers; creatine kinase-MB and lactate dehydrogenase, with histopathological cardiac damage. In addition, CP caused cardiac oxidative stress, manifested by significant increased tissue lipid peroxidation product; malondialdehyde and nitric oxide, with significant decrease in tissue antioxidants as reduced glutathione, superoxide dismutase and catalase compared to control. Furthermore, CP significantly increased tissue proinflammatory cytokines; TNF-α and IL-6, as well as upregulated the apoptotic marker; caspase 3 compared to control. MOR/CP combination significantly deteriorated all tested parameters compared to CP alone. In MCF-7 breast cancer cells, administration of MOR in concentrations of 0.1, 1, 10 or 30 μM concomitantly with 1 or 10 μM CP caused dose-dependent reduction in CP-induced cytotoxicity in vitro. In conclusion, MOR administration might deteriorate CP-induced cardiotoxicity during cancer chemotherapy through oxidant, pro-inflammatory and apoptotic mechanisms, and might reduce CP chemotherapeutic efficacy.