Abstract
P19, a semi-synthetic analog of sesquiterpene lactone ‘Parthenin’, is a promising template to develop into novel anti-cancer leads. P19 induced robust cell death in human leukemia cell lines compared to normal cells when observed after 48h treatment with IC50 of 3.5 μM in HL-60 cells to that of 35 μM in human normal gingival fibroblast cells. Mechanistic studies into HL-60 cells death after 6 h exposure to 10 μM P19 were investigated. It killed cells by apoptosis consequent to robust generation of NO through enhanced expression of iNOS. N-acetyl-L-cysteine (NAC) and s-methyl isothiourea (sMIT) suppressed apoptosis equipotently by inhibiting endogenous NO formation. P19 disrupted mitochondrial functions by altering Bax/Bcl2 ratio, cytosolic Bid loss, Drp1 over expression, Bax and cytochrome c translocation leading predominantly to caspase-9 activation. P19 also translocated AIF from mitochondria to the nucleus which may further potentiate caspases-independent cell death, because pan caspase inhibitor offered incomplete protection. On the contrary, activation of caspase-8 was augmented with concomitant selective enhanced expression of apical death receptor DR4 rather than TNFR1 and FASR. Activation of pre-executioner caspases positively regulated the activation of caspase-3 leading to PARP-1 cleavage and therefore, DNA fragmentation. Down-regulation of activator TNFR1 and transactivator PARP-1 of NF-κB with attendant decreased expression of both the subunits p50 and p65 of NF-κB argue against the plausible involvement of NF-κB as a transcription factor in the induction of iNOS. Further, P19 potently inhibited pro-survival proteins pSTAT-3 and survivin that are overtly expressed in cancer cells. The multimodal proapoptotic features of P19 raises its potential usefulness as a promising anti-cancer therapeutic.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A13
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