Muscella A, Vetrugno C, Biagioni F, Calabriso N, Calierno M T, Fornai F, De Pascali S A, Marsigliante S, Fanizzi F P
Laboratory of Cell Pathology, Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
Neuropathology Unit, Institute of Experimental Neurology and Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Br J Pharmacol. 2016 Sep;173(17):2633-44. doi: 10.1111/bph.13543. Epub 2016 Jul 22.
It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of [Pt(O,O'-acac)(γ-acac)(DMS)] ([Pt(DMS)]), a new platinum drug for non-genomic targets, on human renal carcinoma and compared them with those of the well-established anticancer drug, cisplatin.
Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki-1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs.
Treatment of the Caki-1 cells with cisplatin or [Pt(DMS)] resulted in a dose-dependent inhibition of cell survival, but the cytotoxicity of [Pt(DMS)] was approximately fivefold greater than that of cisplatin. [Pt(DMS)] was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with [Pt(DMS)] decreased VEGF, MMP1 and MMP2 expressions in tumours.
The antiangiogenic and antitumour activities of [Pt(DMS)] provide a solid starting point for its validation as a suitable candidate for further pharmacological testing.
人们认为抗癌化疗药物的作用机制主要是直接抑制肿瘤细胞增殖。在肿瘤标本中，内皮细胞增殖率增加，这表明抗癌药物的治疗效果也可能归因于对肿瘤血管生成的抑制。因此，我们研究了一种针对非基因组靶点的新型铂类药物[Pt(O,O'-acac)(γ-acac)(DMS)]（[Pt(DMS)]）对人肾癌的潜在作用，并将其与成熟的抗癌药物顺铂进行比较。
通过将Caki-1细胞注射到BALB/c裸鼠体内建立肾细胞癌异种移植模型，研究肿瘤生长、肿瘤细胞增殖和微血管密度。还使用人脐静脉内皮细胞（HUVECs）研究了化合物的抗血管生成潜力。
用顺铂或[Pt(DMS)]处理Caki-1细胞导致细胞存活呈剂量依赖性抑制，但[Pt(DMS)]的细胞毒性比顺铂大大约五倍。在体内抑制肿瘤生长、增殖和血管生成以及体外抑制内皮细胞迁移、管腔形成和MMP1、MMP2及MMP9分泌方面，[Pt(DMS)]比顺铂有效得多。然而，顺铂对HUVECs具有更大的细胞毒性，但不影响内皮细胞的管腔形成或迁移。此外，用[Pt(DMS)]处理异种移植小鼠可降低肿瘤中VEGF、MMP1和MMP2表达。
[Pt(DMS)]的抗血管生成和抗肿瘤活性为其作为进一步药理测试的合适候选药物的验证提供了坚实的起点。
