Abstract
Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 µM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118’s effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials.
Highlights
Limited efficacy in terms of impact on overall patient survival, toxicity and drug resistance is the major limitation and challenge of present chemotherapy
The results indicated that FL118 is not a better DNA topoisomerase 1 (Top1) inhibitor than SN-38
We show the results derived from the highest concentration of SN-38 (1 mM) that can be reached by irinotecan in vivo (Fig. 1b)
Summary
Limited efficacy in terms of impact on overall patient survival, toxicity and drug resistance is the major limitation and challenge of present chemotherapy. Studies have revealed that the antiapoptotic protein survivin, a unique member in the inhibitor of apoptosis (IAP) family, is a pivotal molecule at the junction of cancer cell survival and division networks [1,2,3] and a critical inherent and induced drug/radiation resistance factor for various cancer types during treatment [4,5,6,7,8,9,10,11,12]. Cancer cells with stem cell-like expression profiles possess three characteristics: increased IAP expression, activated mitotic spindle checkpoint proteins, and elevated expression of cell cycle control proteins [18]. Survivin is a key member in the IAP family and possesses all three characteristics: apoptosis inhibition, mitotic control, and cell cycle promotion [4,19,20]. Development of novel survivin inhibitors may overcome the challenging issues of drug/radiation resistance and cancer relapse
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