The antitumor activity of CYB-L10, a human topoisomerase IB catalytic inhibitor

Qian Yu,Yu Chen,Hui Yang,Hong-Li Zhang,Keli Agama,Yves Pommier,Lin-Kun An

doi:10.1080/14756366.2018.1516651

Qian Yu, Yu Chen + Show 5 more

Open Access

https://doi.org/10.1080/14756366.2018.1516651

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Abstract

DNA topoisomerase IB (TOP1) is a validated target for discovery and development of antitumor agents. Four TOP1 poisons are clinically used for tumor treatment now. In spite of their effectiveness in solid tumors, these camptothecin (CPT) poisons suffer from many shortcomings. Therefore, many investigations have focused on the discoveries of non-CPT poisons and catalytic inhibitors. Herein, we systematically study the antitumor activity of CYB-L10, a novel indolizinoquinolinedione TOP1 catalytic inhibitor discovered in our laboratory. The results indicated that CYB-L10 mainly acts on TOP1 in cancer cells and is not a substrate of the P-glycoprotein. In addition, CYB-L10 can induce apoptosis of HCT116 cells, shows high cytotoxicity against 60 human clinical cancer cell lines (NCI60) with the mean-graph midpoint for growth inhibition of all cancer cell lines of 0.050 µM concentration and obvious antitumor efficiency in vivo in the HCT116 xenograft model.

Highlights

DNA topoisomerase IB (TOP1) is an essential enzyme that controls the DNA topology structure in many cellular metabolic processes, including replication, transcription, and recombination[1–4]
TOP1 catalytic inhibitors act at the upstream stage of the catalytic DNA cleavage reaction of enzymes, and prevent the formation of TOP1cc[13–16]
Athymic nude mice bearing the nu/nu gene were obtained from Laboratory Animal Center of Sun Yat-sen University and maintained in pathogen-free conditions to establish the model of xenografts of HCT116

Summary

Introduction

DNA topoisomerase IB (TOP1) is an essential enzyme that controls the DNA topology structure in many cellular metabolic processes, including replication, transcription, and recombination[1–4]. Inhibition of TOP1 catalytic activity or trapping of TOP1cc can result in DNA damage, which triggers apoptotic mechanisms and other cell death processes[6–8]. TOP1 catalytic inhibitors act at the upstream stage of the catalytic DNA cleavage reaction of enzymes, and prevent the formation of TOP1cc[13–16]. In spite of their effectiveness in solid tumors, CPT poisons suffer from many shortcomings, including bone marrow dose-limiting toxicity, severe gastrointestinal toxicity[17], poor solubility, chemically instability under physiological pH, and drug efflux-mediated resistance[10]. The indolizinoquinolinedione derivatives have been discovered as a new class of TOP1 catalytic inhibitors[13,15,22], which can inhibit TOP1 catalytic cleavage reaction, and prevent the formation of TOP1cc[13]. We report the activity of CYB-L10 in vitro against 60 clinical cancer cell lines and in vivo in HCT116 xenograft mice model

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Results and discussion

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