1. Academic Validation
  2. Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

  • Chem Sci. 2020 Feb 25;11(12):3215-3222. doi: 10.1039/c9sc05997k.
Xinming Li 1 Yanan Hou 1 Jintao Zhao 1 Jin Li 1 Song Wang 1 Jianguo Fang 1
Affiliations

Affiliation

  • 1 State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University Lanzhou Gansu 730000 China fangjg@lzu.edu.cn.
Abstract

Cancer cells are vulnerable to Reactive Oxygen Species (ROS) due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of Cancer. We report a novel seleno-prodrug of gemcitabine (Gem), Se-Gem, and evaluated its activation and biological effects in Cancer cells. Se-Gem was prepared by introducing a 1,2-diselenolane (a five-membered cyclic diselenide) moiety into the parent drug Gem via a carbamate linker. Se-Gem is preferably activated by glutathione (GSH) and displays a remarkably higher potency than Gem (up to a 6-fold increase) to a panel of Cancer cell lines. The activation of Se-Gem by GSH releases Gem and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG (oxidized GSH) and ROS via redox cycling reactions. Thus Se-Gem may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of Se-Gem as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency via a combination of chemotherapy and oxidative stress.

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