Laboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology ''L. Spallanzani'', University of Pavia, via Ferrata 9, 27100, Pavia, Italy.
Laboratory of General Physiology, Department of Biology and Biotechnology ''L. Spallanzani'', University of Pavia, 27100, Pavia, Italy.
Cell Mol Neurobiol. 2021 Apr;41(3):563-587. doi: 10.1007/s10571-020-00873-8. Epub 2020 May 19.
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 [Ca], in the present in vitro study we compared CDDP and PtAcacDMS effects on apoptosis and intracellular Ca 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 Ca imaging. The results confirmed that (i) platinum compounds may induce cell death through an aberrant increase in [Ca] and (ii) PtAcacDMS exerted stronger cytotoxic effect than CDDP, associated to a larger increase in resting [Ca]. 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.
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 会引起多种副作用和耐药性。[Pt（O，O'-acac）（γ-acac）（DMS）]，即 PtAcacDMS，是一种新的铂（II）配合物，在金属的配位球中含有两个乙酰丙酮（acac）和一个二甲基硫（DMS），最近已被合成，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，同时在体内和体外也显示出强大的抗肿瘤和抗血管生成活性。因此，基于许多化疗药物通过异常增加[Ca]诱导癌细胞死亡的知识，在本体外研究中，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 Ca 动力学的影响，应用了一系列互补技术，即流式细胞术、免疫细胞化学、电子显微镜、Western blot、qRT-PCR 和荧光 Ca 成像。结果证实（i）铂化合物可能通过异常增加[Ca]诱导细胞死亡；（ii）PtAcacDMS 比 CDDP 具有更强的细胞毒性作用，与静息[Ca]的增加更大有关。这些发现证实了将 PtAcacDMS 用作改善基于铂的胶质母细胞瘤化疗的有前途的方法，无论是通过诱导化疗增敏还是降低对 CDDP 治疗有抗性的细胞系的化疗耐药性。
