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.
BACKGROUND
Irinotecan 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.


METHODS
Colon 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.


RESULTS
Both 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.


CONCLUSIONS
Our 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.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. david.westover@roswellpark.org.
David
D
Westover
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. xiang.ling@roswellpark.org.|Canget BioTekpharma, LLC, Buffalo, NY, 14203, USA. xiang.ling@roswellpark.org.
Xiang
X
Ling
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. yhlam1992@gmail.com.
Hong
H
Lam
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. welch11@canisius.edu.
Jacob
J
Welch
Center for Drug Discovery, RTI International, Research Triangle Park, NC, 27709, USA. cjin@rti.org.
Chunyang
C
Jin
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier1; Institut régional du Cancer Montpellier, F-34298, Montpellier, France. celine.gongora@inserm.fr.
Celine
C
Gongora
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier1; Institut régional du Cancer Montpellier, F-34298, Montpellier, France. maguy.delrio@icm.unicancer.fr.
Maguy
M
Del Rio
Center for Drug Discovery, RTI International, Research Triangle Park, NC, 27709, USA. durhamwani@earthlink.net.
Mansukh
M
Wani
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA. fengzhi.li@roswellpark.org.
Fengzhi
F
Li
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007212:Indolizines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059003:Topoisomerase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
C578515:7-ethyl-7-hydroxy-10H-1,3-Dioxolo(4,5-g)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-8,11(7H,12H)-dione; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D052117:Benzodioxoles; D007212:Indolizines; D009363:Neoplasm Proteins; D059003:Topoisomerase Inhibitors; D000077146:Irinotecan; D002166:Camptothecin