Abstract
The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the P-glycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.
Highlights
IntroductionSurvivin is the smallest (molecular weight 16.5 kDa) member of the IAP (Inhibitor of Apoptosis Protein) family[1–2]
Survivin is the smallest member of the IAP (Inhibitor of Apoptosis Protein) family[1–2]
(CPC)[6–7]; (c) it widely participates in tumorigenesis signaling pathways such as Akt, p53, Wnt-2 and MDM2[8–10]; (d) it is highly expressed in most types of human cancer cells and embryonic tissues where rapid cell growth is needed, but has very low expression in normal adult differentiated tissues[11–12]; (e) its expression level is closely correlated with tumor metastasis, poor disease prognosis, and high risk of chemo/radio-resistance[8,11,13–17]
Summary
Survivin is the smallest (molecular weight 16.5 kDa) member of the IAP (Inhibitor of Apoptosis Protein) family[1–2]. It is a unique anti-tumor therapy target because: (a) it acts as an essential anti-apoptosis guard which protects cells from the apoptotic cascade by binding to the activated caspases and neutralizing proapoptotic receptor[3–5]; (b) it is a key regulator of mitosis as a component of the chromosomal passenger complex (CPC)[6–7]; (c) it widely participates in tumorigenesis signaling pathways such as Akt, p53, Wnt-2 and MDM2[8–10]; (d) it is highly expressed in most types of human cancer cells and embryonic tissues where rapid cell growth is needed, but has very low expression in normal adult differentiated tissues[11–12]; (e) its expression level is closely correlated with tumor metastasis, poor disease prognosis, and high risk of chemo/radio-resistance[8,11,13–17]. It is important to develop novel selective survivin inhibitors that can overcome clinically relevant MDR
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