Cisplatin (CDDP) is one of the most effective chemotherapeutic agents, used for the treatment of diverse tumors, including neuroblastoma and glioblastoma. CDDP induces cell death through different apoptotic pathways. Despite its clinical benefits, CDDP causes several side effects and drug resistance.[Pt(O,O'-acac)(γ-acac)(DMS)], namely PtAcacDMS, a new platinum(II) complex containing two acetylacetonate (acac) and a dimethylsulphide (DMS) in the coordination sphere of metal, has been recently synthesized and showed 100 times higher cytotoxicity than CDDP. Additionally, PtAcacDMS was associated to a decreased neurotoxicity in developing rat central nervous system, also displaying great antitumor and antiangiogenic activity both in vivo and in vitro. Thus, based on the knowledge that several chemotherapeutics induce cancer cell death through an aberrant increase in [Ca2+]i, in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca2+ dynamics in human glioblastoma T98G cells, applying a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, electron microscopy, Western blotting, qRT-PCR, and epifluorescent Ca2+ imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca2+]i and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca2+]i. These findings corroborate the use of PtAcacDMS as a promising approach to improve Pt-based chemotherapy against gliomas, either by inducing a chemosensitization or reducing chemoresistance in cell lineages resilient to CDDP treatment.

中文翻译：

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[Pt(O,O'-acac)(γ-acac)(DMS)]：克服顺铂诱导的 T98G 胶质瘤细胞副作用和耐药性的替代策略。

顺铂 (CDDP) 是最有效的化疗药物之一，用于治疗多种肿瘤，包括神经母细胞瘤和胶质母细胞瘤。CDDP 通过不同的凋亡途径诱导细胞死亡。尽管具有临床益处，但 CDDP 会导致多种副作用和耐药性。 [Pt(O,O'-acac)(γ-acac)(DMS)]，即 PtAcacDMS，一种含有两种乙酰丙酮 (acac) 的新型铂 (II) 络合物和金属配位球中的二甲基硫醚 (DMS)，最近被合成并显示出比 CDDP 高 100 倍的细胞毒性。此外，PtAcacDMS 与发育中的大鼠中枢神经系统的神经毒性降低有关，在体内和体外也显示出巨大的抗肿瘤和抗血管生成活性。因此，基于几种化学治疗剂通过 [Ca2+]i 的异常增加诱导癌细胞死亡的知识，在目前的体外研究中，我们比较了 CDDP 和 PtAcacDMS 对人胶质母细胞瘤 T98G 细胞凋亡和细胞内 Ca2+ 动力学的影响，应用一组互补的技术，即流式细胞术、免疫细胞化学、电子显微镜、蛋白质印迹、qRT-PCR 和表面荧光 Ca2+ 成像。结果证实，(i) 铂化合物可能通过 [Ca2+]i 的异常增加诱导细胞死亡，(ii) PtAcacDMS 发挥比 CDDP 更强的细胞毒性作用，与静息 [Ca2+]i 的更大增加相关。这些发现证实了使用 PtAcacDMS 作为改善基于 Pt 的化学疗法对抗神经胶质瘤的有希望的方法，