Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents

Chao Yang; An-Jie Xia; Cheng-Hao Du; Ming-Xing Hu; You-Ling Gong; Rong Tian; Xin Jiang; Yong-Mei Xie

doi:10.3389/fphar.2022.1014854

Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents

Front Pharmacol. 2022 Nov 23:13:1014854. doi: 10.3389/fphar.2022.1014854. eCollection 2022.

Authors

Chao Yang^{1

2

3}, An-Jie Xia¹, Cheng-Hao Du⁴, Ming-Xing Hu¹, You-Ling Gong⁵, Rong Tian⁶, Xin Jiang⁷, Yong-Mei Xie¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China.
² Cognitive Impairment Ward of Neurology Department, The Third Affiliated Hospital of Shenzhen University Medical College, Shenzhen, Guangdong, China.
³ Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
⁴ Department of Biological Sciences, USC Dana and David Dornsife College of Letters, Arts and Sciences, Los Angeles, CA, United States.
⁵ Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁶ Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁷ Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Abstract

7-Ethyl-10-hydroxycamptothecin (SN38), a highly potent metabolite of irinotecan, has an anticancer efficacy 100-1000 folds more than irinotecan in vitro. However, the clinical application of SN38 has been limited due to the very narrow therapeutic window and poor water solubility. Herein, we report the SN38-glucose conjugates (Glu-SN38) that can target cancer cells due to their selective uptake via glucose transporters, which are overexpressed in most cancers. The in vitro antiproliferative activities against human cancer cell lines and normal cells of Glu-SN38 were investigated. One of the conjugates named 5b showed high potency and selectivity against human colorectal cancer cell line HCT116. Furthermore, 5b remarkably inhibited the growth of HCT116 in vivo. These results suggested that 5b could be a promising drug candidate for treating colorectal cancer.

Keywords: 7-ethyl-10-hydroxycamptothecin; anticancer; colorectal cancer; glucose conjugates; warburg effect.