Résumé
The current standard care for metastatic colorectal cancer is combination of leucovorin, 5-fluorouracil, and irinotecan. Irinotecan is a semisynthetic analogue of the alkaloid camptothecin and functions by inducing DNA double-strand breaks through inhibition of topoisomerase I (Top1) activity. The camptothecin-derived Top1 inhibitors irinotecan and topotecan are effective anti-cancer agents that are currently utilized as first-line therapies in several human cancers. Unfortunately, resistance to these agents usually develops during treatment, often through upregulation of the drug efflux pump ABCG2, an ATP-binding cassette transporter. By increasing the rate of drug export, ABCG2 decreases the amount of irinotecan or topotecan that accumulates intracellularly, thereby protecting cancer cells from the cytotoxic effects of these drugs. Therefore, a camptothecin derivative that is also a poor substrate for ABCG2 could potentially overcome ABCG2-induced irinotecan resistance and restore therapeutic efficacy. Our lab recently reported on a novel camptothecin derivative, FL118, which shows strong anti-cancer activity both in vitro and in vivo. Here we report the ability of FL118 to overcome irinotecan resistance. Several irinotecan-resistant colon cancer cell lines derived from HCT116 were treated with either FL118 or SN38, the active metabolite of irinotecan. We observed a decrease in the potency of SN38 in irinotecan-resistant cells that overexpressed ABCG2 compared to cells that did not overexpress ABCG2. In contrast, this loss of potency was not observed for FL118. To confirm that the decrease in potency was ABCG2-dependent, HCT116-A2, an ABCG2 overexpressing cell line, was treated with SN38 or FL118 in the presence or absence of Ko143, an ABCG2 inhibitor. We observed that Ko143 could restore potency to SN38 in HCT116-A2 cells, confirming that irinotecan resistance in HCT116-A2 cells is mediated by ABCG2. However, Ko143 could not modulate the potency of FL118, further suggesting that FL118 is not affected by ABCG2 activity. Similar results were observed in studies with anti-ABCG2 shRNA. Based on these observations, we conclude that FL118 is not a substrate for ABCG2, and that further testing is warranted to determine whether FL118 would be an effective anti-cancer agent for patients with irinotecan-resistant colorectal cancer overexpressing ABCG2.
Citation Format: David Westover, Xiang Ling, Xiaojun Liu, Hong Lam, Celine Gongora, Maguy Del Rio, Fengzhi Li. The novel camptothecin derivative and IAP inhibitor FL118 is an effective treatment for irinotecan-refractory colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 829. doi:10.1158/1538-7445.AM2014-829