TEXAS STATE UNIVERSITY
New research conducted in part at Texas State University has identified a metabolic compound in fungus that exhibits potent anti-cancer properties.
An international research team — including Alexander Kornienko, Ph.D., a professor in the Department of Chemistry and Biochemistry at TXST and holder of the Denise M. Trauth Endowed Presidential Research Professorship, and Sachin B. Wagh, Ph.D., a postdoctoral researcher at TXST — conducted the study, resulting in two peer-reviewed papers.
“New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling in cancer cells” is published in the journal Scientific Reports, and “Sphaeropsidin A C15-C16 Cross-Metathesis Analogues with Potent Anticancer Activity” is published in the journal Chemistry Europe.
“Our original finding involved the identification of a compound from fungi that makes cancer cells shrink, which leads to an irreversible process of cell death known as apoptosis,” Kornienko said. “We were able to generate synthetic derivatives of this compound, which kill cancer cells at concentrations up to five times lower compared to the natural compound.
“This means you need to use much less of the compound to achieve the desired effect against cancer allowing for the reduction of toxicity to normal tissues,” he said. “Currently, we are in the process of synthesizing a larger quantity of our most po- tent synthetic derivative for testing in mouse models of human cancer.”
Diplodia cupressi is a common fungus that causes blight in conifer trees in northeastern parts of North America. The researchers discovered that a compound naturally produced by this fungus, sphaeropsidin A (SphA), effectively kills cancer cells. Cancer cells avoid natural cell death — apoptosis — by using a process known as regulatory volume increase. This leads to unchecked cancer cell growth. SphA overcomes this apoptosis resistance in cancer cells by inducing cellular shrinkage by impairing regulatory volume increase.
On its own, SphA has a broad toxicity to animal cells that limits its usefulness as a cancer treatment. This prompted the research team to develop 17 new synthetic versions of the compound with the goal of identifying versions that were effective against cancer cells but less likely to damage healthy cells. Some of these lab-produced versions of SphA proved to be more potent than the original compound, meaning dosage could be lowered while still achieving the same anti-cancer effects. Furthermore, several of these compounds triggered severe swelling in the cancer cells’ endoplasmic reticulum — a network of membranes inside the cell — ultimately leading to the death of the cancer cells. This additional anti-cancer property was new to the synthetic compounds and not observed in the natural product.
The novel cell-killing mechanisms of these new SphA derivatives may potentially become valuable anti-cancer agents to overcome cancer cells that are resistant to chemotherapy and other cancer treatments.
TXST’s Kevin Lewis, Ph.D., David Schilter, Ph.D., and research assistants Iram Majeed, Robert Scott, Annie R. Hooper and Vladimir A. Maslivetc contributed to the studies.
