Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Breast Cancer. 2022 Mar;29(2):260-273. doi: 10.1007/s12282-021-01310-4. Epub 2021 Nov 1.
Vasculogenic mimicry (VM) is one of the most important causes of breast cancer metastasis and resistance against drugs. The cancer stem cells (CSCs) are known as essential factors for VM formation. In this study, the effects of melatonin, Apatinib, and a combination of Apatinib/melatonin on VM formation were investigated by breast CSCs from breast cancer cell line.
The percentage of CSCs was determined in two breast cancer cell lines (MCF-7 and MDA-MB-231) by flow cytometry. The effects of Apatinib, melatonin, and a combination of Apatinib/melatonin were evaluated on proliferation and viability, migration and invasion, apoptosis, and VM formation in MDA-MB-231 cells. Moreover, expression levels of the involved proteins in cancer cell proliferation and viability, CSCs, migration and invasion, and VM formation were evaluated by real-time polymerase chain reaction (RT-PCR) and western blotting methods.
Results of the present study showed that melatonin and Apatinib reduced survival rate of CSCs in a dose- and time-dependent manner. Apatinib, melatonin, and a combination of Apatinib/melatonin inhibited proliferation of breast CSCs (P ≤ 0.001). Formation of VM was decreased in the MDA-MB-231 cancer cell line treated with Apatinib and combination of Apatinib/melatonin. Apatinib and combination of Apatinib/melatonin reduced invasion of breast CSCs (P ≤ 0.0001). Expression of vascular endothelial VE-cadherin, ephrinA2 receptor (EPHA2), p-PI3K/phosphoinositide-3 kinase (PI3K) and phospho-AKT (p-AKT)/AKT ratios was decreased under the influence of Apatinib and a combination of Apatinib/melatonin (P ≤ 0.01).
Apatinib or a combination of Apatinib/melatonin may be used to manage patients with breast cancer. However, further studies are needed to identify anti-cancer mechanisms of melatonin and Apatinib for better management of the patients with breast cancer.
血管生成拟态（VM）是乳腺癌转移和耐药的最重要原因之一。癌症干细胞（CSC）被认为是 VM 形成的重要因素。在这项研究中，通过乳腺癌细胞系中的乳腺 CSC 研究了褪黑素、阿帕替尼和阿帕替尼/褪黑素联合对 VM 形成的影响。
通过流式细胞术确定两种乳腺癌细胞系（MCF-7 和 MDA-MB-231）中的 CSC 百分比。评估阿帕替尼、褪黑素和阿帕替尼/褪黑素联合对 MDA-MB-231 细胞增殖和活力、迁移和侵袭、凋亡和 VM 形成的影响。此外，通过实时聚合酶链反应（RT-PCR）和蛋白质印迹法评估参与癌细胞增殖和活力、CSC、迁移和侵袭以及 VM 形成的蛋白表达水平。
本研究结果表明，褪黑素和阿帕替尼以剂量和时间依赖的方式降低 CSC 的存活率。阿帕替尼、褪黑素和阿帕替尼/褪黑素联合抑制乳腺 CSC 的增殖（P≤0.001）。在 MDA-MB-231 癌细胞系中，阿帕替尼和阿帕替尼/褪黑素联合治疗可减少 VM 的形成。阿帕替尼和阿帕替尼/褪黑素联合降低了乳腺 CSC 的侵袭（P≤0.0001）。阿帕替尼和阿帕替尼/褪黑素联合降低了血管内皮 VE-cadherin、ephrinA2 受体（EPHA2）、p-PI3K/磷酸肌醇 3 激酶（PI3K）和磷酸化 AKT（p-AKT）/AKT 比值的表达（P≤0.01）。
阿帕替尼或阿帕替尼/褪黑素联合治疗可能用于管理乳腺癌患者。然而，需要进一步研究以确定褪黑素和阿帕替尼的抗癌机制，以更好地管理乳腺癌患者。
