Scripps Florida Scientists Show Antitumor Agent Can Be Activated by Natural Response to Cell Stress

“There is no proven drug right now with these activities,” said Ben Shen, vice chair of TSRI’s Department of Chemistry and senior author of the new study, “so this points the way toward a new therapeutic opportunity.”

The study, published this week by the journal Proceedings of the National Academy of Sciences, highlights the potential of the natural compound called leinamycin (LNM) E1 for development as a “prodrug,” a medication converted through a metabolic process in the body to become an active therapy.

Shen’s research has focused on developing natural products into potential therapies. As part of this effort, he heads the Natural Products Initiative at TSRI, a library available for screening with 500 pure natural products, 2,000 fractions, and 7,500 crude extracts, prepared from 4,000 Actinomycetals.

Among these are “antitumor antibiotics” like LNM, which are produced by species of the soil dwelling bacterium Streptomyces and are known to impede cancer cell growth and multiplication. Some antitumor antibiotics are already in use as chemotherapy agents.

In the new study, the Scripps Florida team collaborated with scientists at the University of Wisconsin, Madison to examine whether LNM E1 can be activated by reactive oxygen species, which are naturally occurring molecules containing oxygen that play essential roles in cell signaling. During times of stress, levels of reactive oxygen species can rise significantly and may trigger apoptosis or programmed cell death. It is now widely accepted that many cancer cells are, by their very nature, under high oxidative stress.

The results were promising. “Our study shows unambiguously that when LNM E1 is activated by cellular reactive oxygen species, it causes DNA damage and cell death in cancer cells,” said Ming Ma, co-first author of the study with Sheng-Xiong Huang. The team further demonstrated the therapeutic potential of LNM E1 by showing it to be effective against two prostate cancer cell lines, which are known to exist under high oxidative stress and with increased levels of reactive oxygen species.

The study also reveals critical new insights into LNM biosynthesis, setting the stage to tailor intermediate steps in the creation of new LNM analogues.

In addition to Shen, Ma and Huang, other authors of the study, “Leinamycin E1 Acting as an Anticancer Prodrug Activated by Reactive Oxygen Species,” include Dong Yang and Jeremy R. Lohman of TSRI; Bong-Sik Yun, Gudrun Ingenhorst, Yong Huang, Hirak S. Basu, Dawn R. Church, Gong-Li Tang, Jianhua Ju and George Wilding of the University of Wisconsin-Madison.

The work was supported in part by the National Institutes of Health (grant CA106150).

About the Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu/.