Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity?

FL118 is a novel camptothecin (CPT) analogue that possesses exceptional antitumor efficacy in human tumor animal models. To date, two CPT analogues, irinotecan and topotecan, have been approved by the FDA for cancer treatment. FL118 exhibits superior antitumor activity over irinotecan and topotecan, and effectively overcomes the irinotecan- or topotecan-resistant human tumors in animal models. Accordingly, FL118 selectively inhibits the expression of multiple cancer-associated proteins (survivin, Mcl-1, XIAP, cIAP2, MdmX). However, FL118 has hematopoietic toxicity similar to irinotecan and topotecan, suggesting that FL118's hematopoietic toxicity may share a mechanism similar to irinotecan and topotecan. It is known that CPTs including irinotecan, SN-38 (active metabolite of irinotecan) and topotecan are topoisomerase I (Top1) inhibitors. However, the evidence from our studies failed to reveal that FL118 is a better Top1 inhibitor than SN-38. It was documented that Top1 expression level is positively associated with CPTs' sensitivity. Low Top1 expression links to CPTs' resistance. In contrast to these findings, we found that human colorectal tumor sensitivity to FL118 is irrelevant to the expression level of Top1 protein. FL118 can show high antitumor efficacy in Top1-negative tumors, while Top1 highly positive tumors can exhibit FL118 resistance. This suggests that the presence of Top1 target is not critical for FL118 antitumor activity. In other words, targeting Top1 by FL118 may not play a major role for its antitumor efficacy. However, studies indicate that FL118 can bind to, and inhibit Top1 activity. This raises the possibility that inhibition of Top1 by FL118 may predominantly be involved in hematopoietic toxicity, but not in FL118 antitumor activity. In this article, we will summarize existing observations and provide our up-to-date research results to support our opinion on this important topic.