There is an old metaphysical concept that suggests for every poison that nature produces, somewhere it also makes the antidote. Investigators at Oregon State University (OSU) may now be able to extrapolate the metaphysics into reality, as they have recently published findings of a new study that describes a soil-dwelling bacterium producing molecules that induce death in melanoma cells. Results from their investigation were published in the Journal of Biological Chemistry in an article entitled “The Natural Product Mensacarcin Induces Mitochondrial Toxicity and Apoptosis in Melanoma Cells.”
In the U.S. alone, more than 80,000 new melanoma cases are diagnosed each year, and about 9000 melanoma patients die. Men are more likely than women to develop melanoma; the death rate varies by race and ethnicity and is highest among Caucasians.
Natural product discoveries have contributed to many new drug leads. A recent analysis of new medicines approved by the FDA between 1981 and 2014 that showed about half of all small-molecule pharmaceuticals were based on natural products or their derivatives.
The molecule the OSU team recently identified—called mensacarcin—is a natural product and secondary metabolite from the soil bacteria Streptomyces bottropensis. Mensacarcin is a highly oxidized and stereogenic complex molecule that can be obtained in large amounts from these bacteria. The properties of this compound are important as there are few therapies that effectively manage melanoma, the most dangerous form of skin cancer.
“Mensacarcin has potent anticancer activity, with selectivity against melanoma cells,” explained senior study investigator Sandra Loesgen, Ph.D., assistant professor of chemistry at OSU. “It shows powerful antiproliferative effects in all tested cancer cell lines in the U.S. National Cancer Institute's cell line panel, but inhibition of cell growth is accompanied by fast progression into cell death in only a small number of cell lines, such as melanoma cells.”
Specifically, Dr. Loesgen and her colleagues found that mensacarcin targets melanoma cells' mitochondria—the cell's main energy-producing organelle. Mitochondria are also important in cell death signaling, and they have emerged as a potential target for therapy since cancer cell mitochondria are structurally and functionally different from mitochondria of noncancerous cells.
To determine what mensacarcin was doing to melanoma on a subcellular level, the investigators synthesized a fluorescent mensacarcin probe.
“The probe localized to mitochondria within 20 minutes of treatment,” Dr. Loesgen remarked. “The localization together with mensacarcin's unusual metabolic effects in melanoma cells provide evidence that mensacarcin targets mitochondria.”
Live-cell bioenergetic flux analysis showed mensacarcin disturbed energy production and mitochondrial function rapidly.
“Its unique mode of action suggests it may be a useful probe for examining energy metabolism,” Dr. Loesgen noted. “Subsequent experiments revealed that mensacarcin rapidly alters mitochondrial pathways, resulting in mitochondrial dysfunction.”
After careful analysis, the researchers found that mensacarcin’s action within mitochondria leads to the activation of apoptotic pathways in melanoma cells.
“Flow cytometry identified a large population of apoptotic melanoma cells, and single-cell electrophoresis indicated that mensacarcin causes genetic instability, a hallmark of early apoptosis,” Dr. Loesgen concluded. “Mensacarcin's unique mode of action indicates it might represent a promising lead for the development of new anticancer drugs.”