Resistance and Apoptosis

For most of the G4 ligands studied so far, apoptotic cell death could be achieved after several cell cycles in tumor-derived cell lines. The triazine ligand 12459 activates the mitochondrial cell death pathway through alteration of the Bax/Bcl-2 balance, which leads to caspase 3 activation. At short-term, it could be noticed that apoptosis predominates over the appearance of senescent cells for this ligand.  

Some of the JFD elones seleeted for resistanee to 12459 also show overexpression of the Bel-2 protein. In addition, A549 cells transfected by Bcl-2 display resistance to the apoptotic action of 12459. However, Bcl-2 overexpression is not sufficient to confer resistance to the long-term effect of 12459. Thus, 12459-directed senescence is uncoupled from apoptosis, a result that fits in well with the differences observed between JFA2 and JFD clones for longterm and short-term resistance studies. 

As a conclusion to this part, the modest selectivity of 12459 for G4 over duplex DNA may render questionable some of these findings, that is, the relationship between short-term effects and its molecular action against telomeres. Future work to obtain resistant cell lines from other sources and with more selective G-quadruplex ligands, such as telomestatin or pyridine dicarboxamide derivatives will aim to confirm some of the views presented here. 

The major characteristic of the telomere extremity is the presence of a G-rich 3 extension (G-overhang) averaging 150-250 bases in length. The G-overhangs are present on all chromosomal ends and are formed during 

S-phase through a complex mechanism that involves cleavage of the C-strand. G-overhangs have been implicated in the structure of the telomere extremities to create the T-loop that protects chromosome ends from fusion and their degradation has been associated with the onset of replicative senescence and more recently to the deprotection of telomeres though inactivation of proteins from the shelterin complex.  

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Molnar, J., Gyemant, N., Mucsi, I., Molnar, A., Szabo, M., Kortvelyesi, T., Varga, A., Molnar, P., and Toth, G. 2004. Modulation of multidrug resistance and apoptosis of cancer cells by selected carotenoids. In Vivo 18, 237-244. 

A large body of evidence illustrates the complexity of tumor biology on both a cellular and an acellular leveh Examples for cellular factors are the variety of genetic gain-of-function or loss-of-function mutations in key molecules involved in proliferation, multidrug resistance, and apoptosis, which are concertedly responsible for the commonly recognized hallmarks of cancer (Croce 2008 Halazonetis et al. 2008 Varmus et al. 2005). 

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