“THE BIOLOGICAL-CHEMICAL INTERFACE: ANTI-CANCER DRUG DISCOVERY PROJECTS at OLEMISS”

Dr. Nagle’s research focuses on the discovery of new drugs. His program combines natural products chemistry with cutting edge molecular mechanism-targeted bioassay techniques. Dr. Nagle explores the biomedical potential of natural products as new sources of drug leads for the treatment of cancer. He and Dr. Yu-Dong Zhou (National Center for Natural Products Research) have developed new molecular-based bioassays to investigate natural products for their potential to supplement existing chemotherapeutic agents by acting as promoters of tumor differentiation and cell death. Dr. Nagle’s research examines new methods to rapidly detect the presence of potentially useful anticancer agents that target specific biochemical mechanisms involved in the development and spread of tumors.

Dramatic progress during the past two decades has led to the identification of many genes involved in tumorigenesis and cancer progression, the molecular mechanisms underlying how these genes function, as well as the biochemical/physiological conditions required for tumor growth and metastatic spread. These have revolutionized antitumor drug discovery from traditional cytotoxic methods to more mechanism-based molecular-targeted approaches. Specifically, our research is now aimed at the discovery of new non-cytotoxic molecular-targeted antitumor agents.

HYPOXIA-INDUCED TUMOR RESISITANCE TO TREATMENT

Dr. Nagle and Dr. Zhou have developed high-throughput bioassays for inhibitors of hypoxia-induced gene expression in order to discover novel natural products that selectively target hypoxic tumor cells within the solid tumor mass and at poorly vascularized metastatic sites. These hypoxic tumor cells are typically resistant to conventional radiation and certain chemotherapeutic agents. This project uses a luciferase reporter gene under the control of the hypoxia response element recognized by hypoxia-inducible factor 1 (HIF-1). HIF-1 is a hypoxia-inducible transcription factor that induces the expression of cell survival genes under reduced oxygen tension.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS

Drs. Nagle and Zhou have developed drug screening procedures to identify new non-toxic natural products that target breast cancer biology, at the molecular level. This research takes advantage of newly discovered biochemical processes in breast tumors, which can potentially be used to specifically disrupt their growth and spread. The aim of this research is to discover new drugs that will cause adipose-derived breast tumor cells to terminally differentiate into nonmalignant fat cells and then ultimately undergo the process of programmed cell death (apoptosis). The molecular target for anticancer drug discovery project is the nuclear hormone receptor/transcription factor, Peroxisome Proliferator-Activated Receptor-gamma (PPAR). Preliminary studies suggest that substances that activate PPAR can inhibit growth, cause terminal differentiation, and induce apoptosis in human breast tumor cells. New high-throughput molecular-targeted bioassays are being developed for the discovery of novel natural products that act as PPAR activators in human breast tumor cells. This research combines molecular biology with modern chemical methods to discovery new therapeutic options for the treatment of cancer.