Al-Malky Hamdan S, Osman Abdel-Moneim M, Damanhouri Zoheir A, Alkreathy Huda M, Al Aama Jumana Y, Ramadan Wafaa S, Al Qahtani Ali A, Al Mahdi Hadiah B
Pharmacology Department, Faculty of Medicine, KAU, Jeddah, Saudi Arabia.
2Pharmacology Unit, National Cancer Institute, Cairo University, Cairo, Egypt.
Cancer Cell Int. 2019 Jul 24;19:191. doi: 10.1186/s12935-019-0912-0. eCollection 2019.
Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. However, chronic cardiotoxicity and multidrug resistance limit the chemotherapeutic use of DOX.
This study aimed to evaluate the capability of calcium channel blocker diltiazem (DIL) to reverse DOX resistance in breast cancer MCF-7 cells and to confer protection against DOX-induced cardiotoxicity in Wistar rats. For this purpose, we explored the effects of DOX on cell cycle phase distribution and expression of ABCB1, FOXO3a, and p53 genes in the presence and absence of DIL (20 μg/ml) and studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats.
We found that compared with DOX alone treatment, DIL + DOX treatment down regulated the ABCB1 gene expression by > fourfold but up regulated the FOXO3a and p53 genes expression by 1.5 fold. DIL treatment conferred protection against DOX-induced cardiotoxicity, as indicated by a decrease in the levels of the cardiac enzyme creatine kinase MB and malondialdehyde and an increase in the total antioxidant capacity and glutathione peroxidase levels. These biochemical results were further confirmed by the histopathological investigation of cardiac cells, which showed normal cardiac cells with central vesicular nuclei and prevention of DOX-induced disruption of normal cardiac architecture in the DIL to DOX group.
Taken together, our results indicate that DIL treatment can reverse the resistance of breast cancer cells to the therapeutic effects of DOX and can protect against DOX-induced cardiotoxicity in rats.
阿霉素（DOX）是治疗乳腺癌最重要的抗癌药物之一。然而，慢性心脏毒性和多药耐药性限制了DOX的化疗应用。
本研究旨在评估钙通道阻滞剂地尔硫䓬（DIL）逆转乳腺癌MCF-7细胞对DOX耐药性的能力，并在Wistar大鼠中赋予其对DOX诱导的心脏毒性的保护作用。为此，我们探讨了在存在和不存在DIL（20μg/ml）的情况下DOX对细胞周期阶段分布以及ABCB1、FOXO3a和p53基因表达的影响，并研究了DIL在雄性Wister大鼠单次注射DOX（15mg/kg）后预防DOX诱导的心脏毒性的能力。
我们发现，与单独使用DOX治疗相比，DIL+DOX治疗使ABCB1基因表达下调超过四倍，但使FOXO3a和p53基因表达上调1.5倍。DIL治疗赋予了对DOX诱导的心脏毒性的保护作用，这表现为心脏酶肌酸激酶MB和丙二醛水平降低，以及总抗氧化能力和谷胱甘肽过氧化物酶水平升高。这些生化结果通过心脏细胞的组织病理学研究得到进一步证实，该研究显示DIL联合DOX组心脏细胞正常，细胞核呈中央泡状，且预防了DOX诱导的正常心脏结构破坏。
综上所述，我们的结果表明，DIL治疗可逆转乳腺癌细胞对DOX治疗效果的耐药性，并可保护大鼠免受DOX诱导的心脏毒性。
