A team led by researchers at Roswell Park Cancer Institute in New York recently discovered that the anticancer camptothecin analogue FL118 is more effective than currently approved therapies for the treatment of lung and colorectal cancers, overcoming the problem of treatment resistance. The study entitled “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”, was published in Molecular Cancer.
Camptothecin is a natural chemical present in a tree used in traditional Chinese medicine that was found to have anticancer properties. Synthetic drugs based on camptothecin have been developed and two analogues of the chemical have been approved by the U.S. Food and Drug Administration (FDA) for cancer chemotherapy, irinotecan and topotecan. Reports of acquired resistance to these drugs have, however, been reported and they are thought to be linked to the increased expression of the efflux transporter ABCG2 (ATP-binding cassette subfamily G isoform 2) leading to an increased intracellular accumulation of the drugs and consequent decrease in potency.
The research team previously discovered a new analogue of camptothecin that has strong anticancer activity – FL118. In the present study, the team compared the potency of FL118 and irinotecan, or its active metabolite SN-38, in relevant models of human cancer, and provided insight into FL118’s ability to overcome the resistance problem. Researchers treated lung and colon cancer cells, with or without ABCG2 overexpression, with FL118 in combination or not with an ABCG2-selective inhibitor called Ko143 or by genetically silencing ABCG2 expression. The team also tested both FL118 and irinotecan in two distinct in vivo human lung and colorectal cancer animal models.
Researchers found that either by genetically modulating ABCG2 or by pharmacological inhibition, FL118 was able to overcome the ABCG2-mediated drug resistance, different from SN-38/ irinotecan. FL118 was also found to extend the time to progression in both human lung and colorectal cancer models by more than 50% in comparison to irinotecan. The team observed that FL118 analogues with polar substitutions exhibited a higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 might be important in bypassing ABCG2-mediated treatment resistance.
The research team concluded that, contrary to irinotecan/SN-38 and topotecan, FL118 is a poor ABCG2 substrate and can effectively overcome ABCG2-mediated drug resistance by becoming insensitive to ABCG2 expression. FL118 was also shown to have better anticancer efficacy than irinotecan in lung and colorectal cancer models. The team believes that FL118 should be further exploited as a therapeutic option in drug-refractory cancers that have a high expression of ABCG2.
“This new study provides additional evidence distinguishing FL118 from irinotecan and topotecan, and our finding that FL118 can bypass ABCG2-mediated resistance opens up the highly attractive prospect of developing FL118 as an orally administered treatment for cancer,” concluded Dr. Fengzhi Li in a news release.