Kielbik Michal, Szulc Izabela, Brzezinska Marta, Bednarska Katarzyna, Przygodzka Patrycja, Sulowska Zofia, Nowak Marek, Klink Magdalena
aInstitute of Medical Biology, Polish Academy of Sciences bDepartment of Gynecology and Gynecologic Oncology, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland.
Anticancer Drugs. 2014 Nov;25(10):1141-51. doi: 10.1097/CAD.0000000000000149.
The most important factors involved in tumor metastasis and angiogenesis are metalloproteinases (MMPs), vascular endothelial growth factor, and multifunctional transforming growth factor β1. These factors are responsible for extracellular matrix degradation, induction of vascular permeability, and enhancement of tumor cells' invasion and metastasis. Elevated expression and secretion of the above-mentioned factors are correlated with the higher aggressiveness of tumors and low patient survival for example, patients with ovarian cancer. Therefore, regulation of the expression, secretion, and activity of these factors is still considered a potent target for therapeutic intervention in cancer patients. Nitric oxide (NO) donors belong to the class of agents with multivalent targeted activities in cancer cells and are considered potential anticancer therapeutics. Our studies have shown that NO donors such as spermine/NO and diethylenetriamine/NO decrease the secretion of vascular endothelial growth factor-A from the OVCAR-3 ovarian cancer cell line, but not from the SK-OV-3 ovarian cancer cell line. The release of MMP-2 from both cell lines was reduced in a soluble guanylate cyclase-dependent manner by spermine/NO and diethylenetriamine/NO. Nevertheless, MMP-2 activity was only affected in SK-OV-3 cells. Both NO donors reduced the transmigration of the ovarian cancer cell lines. We did not observe any significant effect of spermine/NO and diethylenetriamine/NO on mRNA expression of the tested aggressiveness factors. In conclusion, our data indicated that NO donors reduced the metastatic potential of ovarian cancer cells, but its impact is rather low and requires high concentrations of donors. Moreover, both the tested cell lines differed in the susceptibility to NO donors.
肿瘤转移和血管生成中涉及的最重要因素是金属蛋白酶（MMPs）、血管内皮生长因子和多功能转化生长因子β1。这些因素负责细胞外基质降解、诱导血管通透性以及增强肿瘤细胞的侵袭和转移。上述因素的表达和分泌升高与肿瘤的更高侵袭性和患者低生存率相关，例如卵巢癌患者。因此，调节这些因素的表达、分泌和活性仍然被认为是癌症患者治疗干预的有效靶点。一氧化氮（NO）供体属于在癌细胞中具有多价靶向活性的一类药物，被认为是潜在的抗癌治疗药物。我们的研究表明，精胺/NO和二乙烯三胺/NO等NO供体可降低OVCAR-3卵巢癌细胞系中血管内皮生长因子-A的分泌，但对SK-OV-3卵巢癌细胞系则无此作用。精胺/NO和二乙烯三胺/NO以可溶性鸟苷酸环化酶依赖性方式降低了两种细胞系中MMP-2的释放。然而，MMP-2活性仅在SK-OV-3细胞中受到影响。两种NO供体均降低了卵巢癌细胞系的迁移能力。我们未观察到精胺/NO和二乙烯三胺/NO对所测试的侵袭性因子mRNA表达有任何显著影响。总之，我们的数据表明，NO供体降低了卵巢癌细胞的转移潜能，但其影响相当低，且需要高浓度的供体。此外，两种测试细胞系对NO供体的敏感性不同。
