Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Department of Comparative Medicine, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Int J Mol Sci. 2021 Jul 12;22(14):7439. doi: 10.3390/ijms22147439.
Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model.
Female Balb/c mice received rodent chow with vitamin D (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation.
At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg).
Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.
多柔比星（Dox）是三阴性乳腺癌（TNBC）的一线治疗药物，但由于其产生的活性氧介导的心脏毒性，其使用可能受到限制。我们评估了维生素 D 是否可以预防小鼠 TNBC 模型中的 Dox 诱导的心脏毒性。
雌性 Balb/c 小鼠接受维生素 D（1500 IU/kg；载体）或补充额外维生素 D（总量 11500 IU/kg）的鼠粮。将小鼠接种 TNBC 肿瘤，并接受腹腔内 Dox（6 或 10mg/kg）治疗。使用经胸超声心动图评估心功能。用免疫组化和免疫印迹法评估心脏组织中的 4-羟基壬烯醛、NAD（P）H 醌氧化还原酶（NQO1）、C-MYC 和动力相关蛋白 1（DRP1）磷酸化水平。
在 15 至 18 天，用维生素 D+Dox（10mg/kg）治疗的小鼠与用载体治疗的小鼠的平均射血分数、每搏量和短轴缩短率相似，但用维生素 D+Dox（10mg/kg）治疗的小鼠明显大于用 Dox（10mg/kg）治疗的小鼠。Dox（10mg/kg）增加了心脏组织中的 4-羟基壬烯醛、NQO1、C-MYC 和 DRP1 丝氨酸 616 磷酸化，但用维生素 D+Dox（10mg/kg）治疗则没有观察到这些变化。Dox（10mg/kg）和维生素 D+Dox（10mg/kg）治疗均导致肿瘤体积减小。
维生素 D 补充通过减少活性氧和线粒体损伤，降低了 Dox 诱导的心脏毒性，且不降低 Dox 对 TNBC 的抗癌疗效。
