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.
Highlights
Irinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer
We assessed whether there was a difference between relative resistance (RR) for FL118 and SN-38 in HCT116 sublines
The difference between the LogRR of FL118 and SN-38 was statistically significant in both sublines with high ABCG2 expression, SN50 (p = 0.023) and A2 (p = 0.027) (Additional file 1: Table S1)
Summary
Irinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. The second clinically used camptothecin analogue, topotecan, is approved for treatment of ovarian, cervical, and small cell lung cancers [1]. It has been established in the literature that camptothecin analogues function through inhibition of the topoisomerase I (Top1) enzyme. Camptothecin-class compounds target the DNA-Top covalent complex, forming a ternary complex that prevents the dissociation of Top. Camptothecin-class compounds target the DNA-Top covalent complex, forming a ternary complex that prevents the dissociation of Top1 This ternary complex inhibits replication and transcription and leads to the formation of double-strand DNA breaks [4,5]
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