University of Wisconsin-Milwaukee, USA
Title: ROS-Inducible DNA cross-linking agents and their potential applications for cancer therapy
Xiaohua Peng received Ph.D. from the Osnabrueck University, Germany in 2006 and completed her Postdoc training at the Johns Hopkins University. She became an Assistant Professor at the University of Wisconsin-Milwaukee (UWM) in 2009 and is the founding faculty member of UWM’s Milwaukee Institute for Drug Discovery. Her research focus on developing anticancer pro-drugs that can undergo tumor-specifi c activation to release DNA-alkylating or cross-linking agents, such as quinone methides, nitrogen mustard, and nucleoside radicals. She has published over 50 papers in internationally reviewed journals, two book chapters, three invited reviews, and six patents.
DNA interstrand cross-links (ICLs) covalently links two DNA strands, which can block DNA replication, transcription, and any other processes requiring strand separation; thus, they have a strong impact on biological function of nucleic acids. Chemical agents capable of inducing DNA ICLs have attracted growing interest in chemistry, medicine, and chemical biology. Many DNA cross-linking agents are used as anticancer agents. However the host toxicity is the major concern for anticancer chemotherapeutic agents. Over the past few decades, several research groups have developed novel chemical methods for inducing ICL formation, such as photo irradiation, reduction, ROS-induction, or fluoride induction. Among these methods, ROS-induction of ICL formation under physiological conditions is particularly important but probably least developed. Many tumor cells contain high levels of reactive oxygen species (ROS) which makes them distinctively different from normal cells. This distinctive feature of cancer cells was exploited to develop drugs that target tumors while causing less damage to surrounding healthy cells. Particularly, a series of H2O2-activated DNA cross-linking agents were developed that are expected to undergo tumor-specific activation to release DNA-alkylating or cross-linking agents, such as quinone methides and nitrogen mustard. These agents show powerful DNA cross-linking abilities when coupled with H2O2 which is considered as one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. The selectivity was further investigated in normal and leukemic lymphocytes isolated from patients with chronic lymphocytic leukemia (CLL). The details of the chemistry and implications will be discussed.