FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance

Abstract

BackgroundIrinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions.MethodsColon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity.ResultsBoth pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance.ConclusionsOur results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0362-9) contains supplementary material, which is available to authorized users.

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

“…Third, irinotecan, SN-38 and topotecan are the substrates of efflux pump proteins ABCG2/BCRP [83][84][85][86][87] and Pgp/MDR1 [88][89][90][91][92]. In contrast, FL118 is not a substrate for them, and can bypass their resistance [78,93].…”

FL118, a novel camptothecin analogue, suppressed migration and invasion of human breast cancer cells by inhibiting epithelial-mesenchymal transition <i>via</i> the Wnt/β-catenin signaling pathway

“…FL118, a novel camptothecin analogue, was first discovered in high-throughput screening for survivin inhibitors in a previous study by the current authors (16). FL118 was found to display potent anticancer activity against several different types of cancer both in vitro and in vivo (17)(18)(19)(20). Moreover, its antitumor activity was superior to that of several camptothecin analogues, such as irinotecan and topotecan, that have been approved by the FDA for cancer treatment (21,22).…”

“…Moreover, its antitumor activity was superior to that of several camptothecin analogues, such as irinotecan and topotecan, that have been approved by the FDA for cancer treatment (21,22). FL118 is rapidly cleared from circulation and it effectively accumulates in tumors with a long half-life of elimination, suggesting its potential for use in cancer therapy (18,20). However, the effects of FL118 on breast cancer invasion and metastasis have not been reported.…”

Gap junction composed of connexin43 modulates 5-fluorouracil, oxaliplatin and irinotecan resistance on colorectal cancers

“…Irinotecan is also used as a first-line therapy for metastatic colon cancer in combination with other antitumor agents. Unfortunately, resistance to irinotecan has been observed in the clinic (30). Thus, it is clear resistance to chemotherapeutic agents for colon cancers is a great challenge in clinical use.…”