East-West Fusion–Necrosis and Apoptosis Acting in Concert by Demethylcantharidin-Integrated Platinum Complexes

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.