Barbieri F, Sparatore F, Cagnoli M, Bruzzo C, Novelli F, Alama A
Laboratory of Pharmacology and Neuroscience, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132, Genoa, Italy.
Chem Biol Interact. 2001 Mar 14;134(1):27-39. doi: 10.1016/s0009-2797(00)00249-0.
Organotin compounds, particularly tri-organotin, have demonstrated cytotoxic properties against a number of tumor cell lines. On this basis, triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), a quinolizidine derivative, was synthesized and developed as a potential antitumor agent. This tin-derived compound exhibited potent antiproliferative effects on three different human cancer cell lines: teratocarcinoma of the ovary (PA-1), colon carcinoma (HCT-8) and glioblastoma (A-172). Cytotoxic activity was assessed by MTT and cell count assays during time course experiments with cell recovery after compound withdrawal. Significant cell growth inhibition (up to 95% in HCT-8 after 72 h of exposure), which also persisted after drug-free medium change, was reported in all the cell lines by both assays. In addition, the cytocidal effects exerted by IST-FS 29 appeared more consistent with necrosis or delayed cell death, rather than apoptosis, as shown by morphologic observations under light microscope, DNA fragmentation analysis and flow cytometry. In the attempt to elucidate whether this compound might affect genes playing a role in G1/S phase transition, the expressions of p53, p21(WAF1), cyclin D1 and Rb, mainly involved in response to DNA-damaging stress, were analyzed by Western blot. Heterogeneous patterns of expression during exposure to IST-FS 29 were evidenced in the different cell lines suggesting that these cell-cycle-related genes are not likely the primary targets of this compound. Thus, the present data seem more indicative of a direct effect of IST-FS-29 on macromolecular synthesis and cellular homeostasis, as previously hypothesized for other organotin complexes.
有机锡化合物，特别是三有机锡，已对多种肿瘤细胞系表现出细胞毒性。在此基础上，合成并开发了一种喹诺里西啶衍生物三乙基锡（IV）羽扇豆基硫化物盐酸盐（IST-FS 29）作为一种潜在的抗肿瘤药物。这种锡衍生化合物对三种不同的人类癌细胞系表现出强大的抗增殖作用：卵巢畸胎瘤（PA-1）、结肠癌（HCT-8）和胶质母细胞瘤（A-172）。在撤药后细胞恢复的时间进程实验中，通过MTT和细胞计数测定评估细胞毒性活性。两种测定方法均报告在所有细胞系中均有显著的细胞生长抑制（暴露72小时后HCT-8中高达95%），在更换无药物培养基后这种抑制作用仍然持续。此外，如光学显微镜下的形态学观察、DNA片段化分析和流式细胞术所示，IST-FS 29所产生的杀细胞作用似乎更符合坏死或延迟细胞死亡，而不是凋亡。为了阐明该化合物是否可能影响在G1/S期转换中起作用的基因，通过蛋白质印迹分析了主要参与对DNA损伤应激反应的p53、p21（WAF1）、细胞周期蛋白D1和Rb的表达。在暴露于IST-FS 29期间，不同细胞系中出现了异质性的表达模式，这表明这些与细胞周期相关的基因不太可能是该化合物的主要靶点。因此，目前的数据似乎更表明IST-FS-29对大分子合成和细胞稳态有直接影响，正如先前对其他有机锡配合物所假设的那样。
