Laboratory of Cell Physiology, Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy.
Laboratory of Cell Pathology, Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy.
Biomolecules. 2019 Mar 6;9(3):92. doi: 10.3390/biom9030092.
We have demonstrated the cytotoxic effects of [Pt(,'-acac)(γ-acac)(dimethyl sulfide (DMS))] on various immortalized cell lines, in primary cultures, and in murine xenograft models in vivo. Recently, we also showed that [Pt(-acac)(γ-acac)(DMS)] is able to kill Caki-1 renal cells both in vivo and in vitro. In the present paper, apoptotic and autophagic effects of [Pt(,'-acac)(γ-acac)(DMS)] and cisplatin were studied and compared using Caki-1 cancerous renal cells. The effects of cisplatin include activation of caspases, proteolysis of enzyme poly ADP ribose polymerase (PARP), control of apoptosis modulators B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and BH3-interacting domain death agonist (Bid), and cell cycle arrest in G2/M phase. Conversely, [Pt(,'-acac)(γ-acac)(DMS)] did not induce caspase activation, nor chromatin condensation or DNA fragmentation. The effects of [Pt(,-acac)(γ-acac)(DMS)] include microtubule-associated proteins 1A/1B light chain 3B (LC3)-I to LC3-II conversion, Beclin-1 and Atg-3, -4, and -5 increase, Bcl-2 decrease, and monodansylcadaverine accumulation in autophagic vacuoles. [Pt(,-acac)(γ-acac)(DMS)] also modulated various kinases involved in intracellular transduction regulating cell fate. [Pt(,'-acac)(γ-acac)(DMS)] inhibited the phosphorylation of mammalian target of rapmycin (mTOR), p70S6K, and AKT, and increased the phosphorylation of c-Jun N-terminal kinase (JNK1/2), a kinase activity pattern consistent with autophagy induction. In conclusion, while in past reports the high cytotoxicity of [Pt(,'-acac)(γ-acac)(DMS)] was always attributed to its ability to trigger an apoptotic process, in this paper we show that Caki-1 cells die as a result of the induction of a strong autophagic process.
我们已经证明了[Pt(,'-acac)(γ-acac)(二甲基亚砜（DMS）)]对各种永生化细胞系、原代培养物以及体内小鼠异种移植模型的细胞毒性作用。最近，我们还表明[Pt(-acac)(γ-acac)(DMS)]能够在体内和体外杀死 Caki-1 肾癌细胞。在本文中，我们使用 Caki-1 癌细胞研究并比较了[Pt(,'-acac)(γ-acac)(DMS)]和顺铂的凋亡和自噬作用。顺铂的作用包括激活半胱天冬酶、酶多聚 ADP 核糖聚合酶 (PARP) 的蛋白水解、凋亡调节剂 B 细胞淋巴瘤 2 (Bcl-2)、Bcl-2 相关 X 蛋白 (Bax) 和 BH3 相互作用结构域死亡激动剂 (Bid) 的控制，以及细胞周期停滞在 G2/M 期。相反，[Pt(,'-acac)(γ-acac)(DMS)]不会诱导半胱天冬酶激活，也不会导致染色质浓缩或 DNA 片段化。[Pt(,-acac)(γ-acac)(DMS)]的作用包括微管相关蛋白 1A/1B 轻链 3B (LC3)-I 到 LC3-II 的转化、Beclin-1 和 Atg-3、-4 和 -5 的增加、Bcl-2 的减少以及自噬小体中单丹磺酰尸胺的积累。[Pt(,-acac)(γ-acac)(DMS)]还调节了参与细胞内转导调节细胞命运的各种激酶。[Pt(,'-acac)(γ-acac)(DMS)]抑制哺乳动物雷帕霉素靶蛋白 (mTOR)、p70S6K 和 AKT 的磷酸化，并增加 c-Jun N-末端激酶 (JNK1/2) 的磷酸化，这种激酶活性模式与自噬诱导一致。总之，虽然在过去的报告中，[Pt(,'-acac)(γ-acac)(DMS)]的高细胞毒性总是归因于其触发凋亡过程的能力，但在本文中我们表明，Caki-1 细胞因诱导强烈的自噬过程而死亡。
