Targeting the disturbed redox equilibrium in chronic lymphocytic leukemia by novel reactive oxygen species-catalytic ‘sensor/effector’ compounds

Abstract

Precursor transformation, clonal sustenance, and therapeutic resistance in cancer are significantly mediated by deregulated reactive oxygen species (ROS), which primarily act as DNA-stressors. Here, we demonstrate that elevated ROS in chronic lymphocytic leukemia (CLL) may represent a promising therapeutic target. We designed organochalcogens, which, based on a ‘sensor/effector’ principle, would confer selective cytotoxicity through the generation of intolerably high ROS levels preferentially in CLL cells, as these carry a high-level redox burden. Our novel compounds show an encouraging profile of efficient induction of apoptosis, low normal cell toxicity, and promising chemotherapy synergism. These findings warrant further mechanistic and preclinical studies of this therapeutic principle in CLL.

Keywords:

• CLL
• oxidative stress
• ROS
• redox catalysts
• organochalcogens

Acknowledgements

N.L., the presenter of the above data at the 5th Young Investigators' Meeting on CLL as part of the 8th International Workshop of the GCLLSG, receives stipend support by a joint pharmacology graduate program of Cologne University and Bayer Health Care AG. M.Ha. is supported by the local CECAD initiative. C.J. is supported by the University of Saarland, the Ministry of Economics and Science of Saarland, DFG grant JA1741/2-1, and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 215009 RedCat. M.He. is supported by a DFG grant HE3553/2-1 and the local CECAD initiative, a Max-Eder Junior Group Award of the German Cancer Aid, and the CLL Global Research Foundation.

We thank J Med Chem for permission to present Figures 1(C), 2(B), and 2(C), as they are part of the publication by Doering et al., J Med Chem 2010;53:6954–6963, and protected by copyright law.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal .