Researchers at The Scripps Research Institute (TSRI) and the University of Wisconsin-Madison recently reported that a specific prodrug with antitumor potential can be effective in eliminating prostate cancer cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS) and is entitled “Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species”.
Part of the research conducted at TSRI focuses on the development of natural products of bacterial origin into potential therapies. Some of these products are antitumor antibiotics produced by Streptomyces bacterium species that have the ability to repress cancer multiplication and cell growth. One such antitumor antibiotic is leinamycin (LNM).
LNM biosynthesis has been manipulated resulting in a recombinant strain that generates a LNM biosynthetic intermediate – leinamycin E1 (LNM E1). LNM E1 was developed as a “prodrug”, a medication that is converted through a metabolic process into an active therapy within the body.
LNM can undergo reductive activation in the presence of cellular thiols, leading to antitumor activity. In the study, researchers tested whether LNM could also undergo oxidative activation by cellular reactive oxygen species (ROS).
ROS are naturally occurring molecules that result from oxygen metabolism. They play an important role in cell signaling and, when present in high levels for instance in stress conditions, can induce significant damage to cell structures and trigger apoptosis (programmed cell death). Cancer cells are known to be under high oxidative stress and to have higher ROS levels compared to normal healthy cells. The team therefore proposed that ROS could be used to target cancer cells.
Researchers found that LNM can be activated by ROS leading to cell death. “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 the study’s co-lead author Ming Ma in a news release.
LNM E1 was then tested as an antitumor prodrug in two cell lines of prostate cancer known to have increased ROS levels – LNCaP and DU-145. The team found that LNM E1 was effective against prostate cancer cells, inducing their death and elimination.
The team concluded that LNM E1 can be activated by ROS in cells under cellular stress as is the case of prostate cancer cells, leading to their death. “There is no proven drug right now with these activities,” noted the study’s senior author Dr. Ben Shen, “so this points the way toward a new therapeutic opportunity.”
The team believes that LNM is a promising anticancer therapeutic strategy and that further studies should be conducted to tailor and create new LNM analogues.
