Pang Siu-Kwong, So Wang-Kei, Ho Yee-Ping, Au-Yeung Chik-Fun
Faculty of Applied Science and Textiles, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
Anticancer Agents Med Chem. 2014 Jun;14(5):756-61. doi: 10.2174/1871520614666140127104057.
The different types of cell death occurring in HCT116 colorectal cancer cell after the treatment of cisplatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(demethylcantharidin:DMC) and Pt(R,R-1,2-diaminocyclohexane: DACH)(DMC) were examined. Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) are the two DMC-integrated platinum complexes:Pt(R,R-DACH)(DMC) with the same Pt moiety as oxaliplatin and Pt(NH3)2(DMC) akin to carboplatin. Using the light scattering properties of cells combined with propidium iodide (PI) red fluorescence to distinguish between early apoptotic and necrotic cells, the results confirmed that apoptosis, which triggered by cisplatin, carboplatin and oxaliplatin, was the major type of cell death, while the major DMC-induced cell death type was necrosis. The increase in the necrotic cell population was observed after Pt((NH3)2(DMC) treatment when compared with carboplatin; therefore, the DMC ligand in Pt(NH3)2(DMC) contributing to cell death was demonstrated. However, the DMC ligand in Pt(R,RDACH)( DMC) failed to elevate the necrotic cell population significantly in contrast to oxaliplatin, thus Pt(R,R-DACH) in Pt(R,RDACH)( DMC) dominantly contributed to cell death. The IC50 value (antiproliferative activity) reflects the net effect of drugs on cell proliferation resulting from inhibition of cell growth and division, and induction of cell death. The sub-G1 populations representing the sum of the amounts of late apoptotic cells and necrotic cells after the treatment of cispatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) were found to be not correlated with the corresponding IC50 values;therefore, the rate of cell growth and division inhibition rather than the rate of induction of cell death dictated to the IC50 values. This combined analysis of IC50 values and the sub-G1 population data also reveals that the platinum compounds containing R,R-DACH are most efficient in inhibiting cell growth and division, while carboplatin induces cell death most rapidly. When the Pt-DNA adducts are believed to be major cytotoxic species, the combined analysis of the IC50 values and the sub-G1 population data infers that the R,R-DACH-Pt-1,2-d(GpG) intrastrand cross-links caused by oxaliplatin treatment are more effective in inducing cell growth and division inhibition, while the (NH3)2Pt-1,3- d(GpXpG) intrastrand cross-links caused by carboplatin treatment can trigger cell death more rapidly. The rate of cell growth and division inhibition and the cell death rate induced by the main cisplatin-DNA adducts:(NH3)2Pt-1,2-d(GpG) intrastrand cross-links lie in between.
研究了顺铂、卡铂、奥沙利铂、DMC、Pt(NH₃)₂(去甲斑蝥素:DMC)和Pt(R,R-1,2-二氨基环己烷:DACH)(DMC)处理后HCT116结肠癌细胞中发生的不同类型细胞死亡。Pt(NH₃)₂(DMC)和Pt(R,R-DACH)(DMC)是两种整合了DMC的铂配合物:Pt(R,R-DACH)(DMC)与奥沙利铂具有相同的铂部分，Pt(NH₃)₂(DMC)类似于卡铂。利用细胞的光散射特性结合碘化丙啶(PI)红色荧光来区分早期凋亡细胞和坏死细胞，结果证实，由顺铂、卡铂和奥沙利铂引发的凋亡是主要的细胞死亡类型，而主要的DMC诱导的细胞死亡类型是坏死。与卡铂相比，Pt((NH₃)₂(DMC)处理后观察到坏死细胞群体增加;因此，证明了Pt(NH₃)₂(DMC)中的DMC配体促成细胞死亡。然而，与奥沙利铂相比，Pt(R,RDACH)(DMC)中的DMC配体未能显著提高坏死细胞群体，因此Pt(R,RDACH)(DMC)中的Pt(R,R-DACH)对细胞死亡起主要作用。IC50值(抗增殖活性)反映了药物对细胞增殖的净效应，该效应源于对细胞生长和分裂的抑制以及细胞死亡的诱导。发现顺铂、卡铂、奥沙利铂、DMC、Pt(NH₃)₂(DMC)和Pt(R,R-DACH)(DMC)处理后代表晚期凋亡细胞和坏死细胞总量的亚G1群体与相应的IC50值不相关;因此，决定IC50值的是细胞生长和分裂抑制率而非细胞死亡率。IC50值和亚G1群体数据的这种综合分析还表明，含R,R-DACH的铂化合物在抑制细胞生长和分裂方面最有效，而卡铂诱导细胞死亡最快。当Pt-DNA加合物被认为是主要的细胞毒性物质时，IC50值和亚G1群体数据的综合分析推断，奥沙利铂处理引起的R,R-DACH-Pt-1,2-d(GpG)链内交联在诱导细胞生长和分裂抑制方面更有效，而卡铂处理引起的(NH₃)₂Pt-1,3-d(GpXpG)链内交联能更快地触发细胞死亡。主要的顺铂-DNA加合物:(NH₃)₂Pt-1,2-d(GpG)链内交联诱导的细胞生长和分裂抑制率及细胞死亡率介于两者之间。
