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

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Abstract

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.

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Abbreviations

CK-MB:

Creatine kinase-MB

CP:

Cisplatin

ELISA:

Enzyme-linked immunosorbent assay

GSH:

Reduced glutathione

IL-6:

Interleukin-6

LDH:

Lactate dehydrogenase

MCF-7:

Human breast cancer cell line named after the acronym of Michigan Cancer Foundation

MDA:

Malondialdehyde

MOR:

Morphine

NO:

Nitric oxide

SOD:

Superoxide dismutase

SRB:

Sulforhodamine B

TNF-α:

Tumor necrosis factor-α

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Funding

This research was funded by Deanship of Scientific Research at Princess Nourah bint Abdulrahman University (Grant No# 240/S/39).

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Authors and Affiliations

  1. Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia

    Azza A. K. El-Sheikh

  2. Department of Pharmacology, Faculty of Medicine, Minia University, El Minia, 61511, Egypt

    Azza A. K. El-Sheikh

  3. Department of Surgery, Faculty of Medicine, Jazan University, Jazan, 45142, Saudi Arabia

    Zenat Khired

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  1. Azza A. K. El-Sheikh
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  2. Zenat Khired
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Correspondence to Azza A. K. El-Sheikh.

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The procedures of the experiments were ethically approved by the Institutional Review Board of Princess Nourah bint Abdulrahman University, Saudi Arabia (IRB number 17-0194).

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El-Sheikh, A.A.K., Khired, Z. Morphine Deteriorates Cisplatin-Induced Cardiotoxicity in Rats and Induces Dose-Dependent Cisplatin Chemoresistance in MCF-7 Human Breast Cancer Cells. Cardiovasc Toxicol 21, 553–562 (2021). https://doi.org/10.1007/s12012-021-09646-1

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  • DOI: https://doi.org/10.1007/s12012-021-09646-1

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