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2002). But similar to our findings there are reports in which IMPDH inhibitors have been shown to cause PARP cleavage in human ovarian carcinoma cell lines (Grusch et al, 1999; Hunakova et al, 2000). Moreover our results clearly demonstrate that caspase-8 is not a requirement for TR induced apoptosis in SiHa, Hep2 and Ca Ski cells. Also a non-significant difference in the protein expression level of AIF was observed in untreated and treated cells therefore ruling out the possibility of involvement of this protein in TR induced apoptosis. It appears to execute apoptosis via the non-receptor mediated caspase activation which is dependent on p53, as we observed a significant increase in p53 expression levels in all the three cell lines. Also there was a significant increase in cytochrome c after TR treatments, which further supports the involvement of mitochondria in TR induced apoptotic signaling pathway. Similar to our findings, the IMPDH inhibitor TR has been shown to induce apoptosis in various leukemic and human colon carcinoma cell lines (Yalowitz et al, 2002; Colovic et al, 2003; De Abreu et al, 2003; Wright et al, 2004). It selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. IMPDH inhibitors are biochemically convenient in inhibiting parallel pathways, thus their antitumor potential is particularly high. In conclusion, our results indicate that TR induces apoptosis via the intrinsic mitochondrial pathway in SiHa, Hep2 and Ca Ski cells. Also, the downregulation of antiapoptotic proteins such as Bcl-2 and Bcl-xL and the upregulation of p53 which accompanied with activation of initiator as well as effector caspases-9, -3 by TR suggest its potential usefulness as a therapeutic for cancer treatment.
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