Bojková Bianka, Kajo Karol, Kisková Terézia, Kubatka Peter, Žúbor Pavol, Solár Peter, Péč Martin, Adamkov Marián
aDepartment of Animal Physiology, Institute of Biology and Ecology, Faculty of Science bDepartment of Medical Biology, Faculty of Medicine, Pavol Jozef Šafárik University, Košice cDepartment of Pathology, Slovak Medical University and St. Elisabeth Oncology Institute, Bratislava dDepartment of Medical Biology eDepartment of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin fClinic of Gynecology and Obstetrics gDepartment of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic.
Anticancer Drugs. 2018 Feb;29(2):128-135. doi: 10.1097/CAD.0000000000000576.
The data from in-vitro and in-vivo studies show that both peroral antidiabetic metformin (MF) and pineal hormone melatonin (MT) inhibit the growth of many cancers, including breast cancer. However, most in-vivo studies used standard-type diet with low fat content. Therefore, in this study, we evaluated the chemopreventive effect of MF and MT in an in-vivo model of breast cancer in rats on a high-fat diet (10% of total fat). Mammary carcinogenesis was induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Chemoprevention with MF (administered in a diet, 0.2%) and MT (administered in tap water, 20 mg/l) was induced 20 days before the carcinogen administration through the termination of the experiment (14 weeks after carcinogen administration). Tumor growth parameters were analyzed together with histopathological examination and immunohistochemical detection of KI67 (proliferation marker), caspase-3, BAX, BCL-2 (apoptosis markers), and CD24 and CD44 (cancer stem cell markers) in mammary tumor samples. The combination of chemopreventive agents decreased tumor incidence by 29%. Cumulative tumor volume was lower in all groups treated with chemoprevention. Histopathology did not show significant changes in high-grade/low-grade tumor ratio. Immunohistochemistry showed increased expression of BAX in the combination group, and caspase-3 expression increased in both MT and combination groups. MT, and particularly the MF and MT combination, inhibited DMBA-induced mammary tumor growth in rats by apoptosis stimulation in cancer cells. Our results indicate that MT supplements in patients treated with MF may have a considerable effect on the incidence of breast cancer.
体外和体内研究数据表明，口服抗糖尿病药物二甲双胍（MF）和松果体激素褪黑素（MT）均能抑制包括乳腺癌在内的多种癌症的生长。然而，大多数体内研究使用的是低脂含量的标准型饮食。因此，在本研究中，我们评估了MF和MT在高脂饮食（总脂肪含量为10%）大鼠乳腺癌体内模型中的化学预防作用。雌性Sprague-Dawley大鼠经7,12-二甲基苯并[a]蒽（DMBA）诱导发生乳腺癌。在给予致癌物前20天开始用MF（以0.2%的比例添加到饮食中）和MT（以20 mg/l的浓度添加到自来水中）进行化学预防，直至实验结束（给予致癌物后14周）。对乳腺肿瘤样本的肿瘤生长参数进行分析，并进行组织病理学检查以及对KI67（增殖标志物）、半胱天冬酶-3、BAX、BCL-2（凋亡标志物）和CD24及CD44（癌症干细胞标志物）进行免疫组化检测。化学预防剂联合使用使肿瘤发生率降低了29%。所有接受化学预防治疗的组的累积肿瘤体积均较小。组织病理学检查未显示高级别/低级别肿瘤比例有显著变化。免疫组化显示联合组中BAX表达增加，MT组和联合组中半胱天冬酶-3表达均增加。MT，尤其是MF与MT联合使用，通过刺激癌细胞凋亡抑制了DMBA诱导的大鼠乳腺肿瘤生长。我们的结果表明，在接受MF治疗的患者中补充MT可能对乳腺癌的发生率有相当大的影响。
