Ahmadi Abdolreza, Hosseini Fatemehsadat, Rostami Mehdi, Soukhtanloo Mohammad
Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
J Steroid Biochem Mol Biol. 2025 Mar;247:106664. doi: 10.1016/j.jsbmb.2024.106664. Epub 2024 Dec 16.
Osteosarcoma (OS), an extremely aggressive form of bone tumor primarily affects young adults. Despite significant advancements in clinical trials, the ability of cancer cells to metastasize and resist apoptosis remains a major challenge. To address these issues, novel therapeutic interventions with high specificity for these processes are essential. Alpha-lipoic acid (ALA), an organosulfur compound derived from octanoic acid, possesses a range of pharmacological properties. This study hypothesizes that ALA would inhibit metastasis and induce cell apoptosis in OS. To evaluate the potential of ALA, its effects on the migration, metastasis, and cell cycle of MG-63 OS cells were assessed, along with its ability to trigger apoptosis. To these aims, MG-63 cells were exposed to varying concentrations of ALA, and cell viability was measured using the alamarBlue assay. The impact of ALA on cell cycle progression, apoptosis, migration, and metastasis was analyzed through flow cytometry, scratch assay, and gelatin zymography. After validating the expression of MMP2, MMP9, VEGF, VEGFR, BAX, BCL-2, and P53 by the GEO database, the expression levels of these genes were examined through quantitative PCR (qPCR). Eventually, molecular docking was employed to simulate the interactions between ALA and matrix metalloproteinase (MMPs). The results demonstrated that ALA significantly inhibited cell migration, induced cell cycle arrest, and promoted apoptosis by upregulating P53 and BAX expression while downregulating BCL-2 levels. Furthermore, ALA was found to suppress the activity and expression of MMP2 and MMP9 and reduce the expression of angiogenesis markers. Notably, ALA interacted directly with the active site of MMP2 and MMP9. These findings suggest that ALA has the potential to be a promising agent with anti-cancer effects on MG-63 cells, warranting further preclinical investigations.
骨肉瘤（OS）是一种极具侵袭性的骨肿瘤形式，主要影响年轻人。尽管临床试验取得了重大进展，但癌细胞转移和抵抗凋亡的能力仍然是一个主要挑战。为了解决这些问题，针对这些过程具有高特异性的新型治疗干预措施至关重要。α-硫辛酸（ALA）是一种源自辛酸的有机硫化合物，具有一系列药理特性。本研究假设ALA会抑制骨肉瘤的转移并诱导细胞凋亡。为了评估ALA的潜力，评估了其对MG-63骨肉瘤细胞迁移、转移和细胞周期的影响，以及其触发凋亡的能力。为了实现这些目标，将MG-63细胞暴露于不同浓度的ALA，并使用alamarBlue测定法测量细胞活力。通过流式细胞术、划痕试验和明胶酶谱分析ALA对细胞周期进程、凋亡、迁移和转移的影响。通过GEO数据库验证MMP2、MMP9、VEGF、VEGFR、BAX、BCL-2和P53的表达后，通过定量PCR（qPCR）检测这些基因的表达水平。最终，采用分子对接来模拟ALA与基质金属蛋白酶（MMPs）之间的相互作用。结果表明，ALA通过上调P53和BAX表达同时下调BCL-2水平，显著抑制细胞迁移，诱导细胞周期停滞并促进凋亡。此外，发现ALA抑制MMP2和MMP9的活性和表达，并降低血管生成标志物的表达。值得注意的是，ALA直接与MMP2和MMP9的活性位点相互作用。这些发现表明，ALA有可能成为对MG-63细胞具有抗癌作用的有前景的药物，值得进一步的临床前研究。
