Experimental Brain Cancer Drug Disrupts Intracellular Endosome Activity

Cancer researchers have described the mechanism by which the low molecular weight compound 5-Benzylglycinyl-amiloride (UCD38B) disrupts the internal regulation of brain cancer (glioma) cells in a manner that triggers the pathway for programmed cell death (apoptosis).

Chemotherapy rarely succeeds in curing brain cancer due to the existence in the tumor of a subpopulation of non-dividing stem cell-like cells that are unaffected by the treatment. These cells, which reside in tumor regions having negligible or no blood supply and minimal oxygen content, remain quiescent for a time then replicate and regenerate the tumor.

Investigators at the University of California, Davis (USA) have been working with the candidate drug UCD38B, which kills both actively growing and quiescent glioma cells. They described the drug's mechanism of action in the January 29, 2015, online issue of the journal Molecular Pharmacology.

The investigators explained that UCD38B triggered an intracellular process of endocytosis that caused 40%–50% of endosomes containing proteins of the urokinase plasminogen activator system (uPAS) to relocate from the area of the cell membrane to mitochondrial regions in the cytoplasm. Components of uPAS have been found to be highly active in many aggressive cancers, including gliomas, as well as metastatic breast, lung, and pancreatic cancers. The improper re-location of the uPAS enzyme complex caused endosomal “mis-trafficking” which corresponded to mitochondrial depolarization with the release and nuclear translocation of apoptosis-inducing factor (AIF) followed by irreversible caspase-independent cell death.

Preliminary studies carried out with a rodent glioma xenograft model showed that a low molecular weight derivative of UCD38B was very effective in destroying the population of hypoxic glioma cells within the tumor without evidence of adverse effects.

“Understanding the drug mechanism of action of UCD38B and its more potent derivatives is the culmination of many years of work of characterizing the processes causing cancer recurrence and developing molecules that target therapeutically resistant cancer cell types,” said senior author Dr. Fredric Gorin, professor of molecular biosciences at the University of California, Davis. “We are hopeful that this new class of drug will one day become an important adjunct to conventional therapies in fighting these especially difficult-to-treat cancers.”

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