By Riya Gandhi ‘22
The aggressive proliferation of glioblastoma cells is characteristic of glioblastoma multiforme (GBM), a fatal cancer of the brain. As much as treatments may help, patients with this cancer typically relapse. Furthermore, radiotherapy and chemotherapy unintentionally target and poison normal proliferating cells, thereby harming the wellbeing of the patients. However, under principle investigator Dr. Yufeng Shi, researchers at the Cancer Biology & Genetics Program at Memorial Sloan Kettering Cancer Center in New York investigated Gboxin, a possible inhibitor of glioblastoma cells in both mice and humans. As this molecule functions in oxidative phosphorylation, researchers discovered that it was possible to infiltrate the mitochondrial membrane of some GBM cells and disrupt metabolic activity. In doing so, the proliferation of GBM is reduced.
To conduct the experiment, Dr. Shi and his team first chemically screened approximately 200,000 compounds to uncover 61 compounds inhibiting high-throughput GMB sphere (HTS) cells. Further tests reduced this number to 17 compounds and one compound in particular, benzimidazolinium Gboxin, was chosen due to its ability to inhibit the growth of HTS cells, but not astrocytes nor mouse embryonic fibroblasts (MEFs). The scientists did not want to inhibit growth of astrocytes and MEFs because they are nonspecific and have anti-mitotic toxicity characteristics. Between 6 to 24 hours of exposure, inhibition by Gboxin occurred, eventually leading to cell cycle arrest for the HTS cells, and ultimately apoptosis. When the researchers continued Gboxin treatment, data revealed that the mitochondrial membrane potential decreased for HTS cells. In addition to this discovery, measurements regarding oxygen consumption of these cells revealed that Gboxin deleted the rate of oxygen consumption in all three cell types, but only MEFs and astrocytes were able to regain the previous rate. Next, the researchers identified that the toxic molecule interacted with respiratory chain proteins. Likewise, the researchers noted that a functional mitochondrial permeability transition pore regulating pH is necessary for the cancer cells to defend themselves against Gboxin. The accumulation of this information prompted Dr. Shi and his colleagues to test Gboxin on mice and GBM patient cultures, which all ultimately demonstrated sensitivity to Gboxin.
From these various experiments, the researchers deduced that human cancer cells from various organs are all susceptible to the infiltration of Gboxin. Pharmacists and other researchers may be able to utilize this new information to develop safer methods to eliminate cancer cells that do not harm the wellbeing of the patient.
- Y. Shi, et. al., Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature, (2019). doi: 10.3892/mmr.2015.4014.
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