GELDANAMYCINS AND THEIR QUINONE MOIETIES INHIBIT CANCER BY ACTING ON MITOCHONDRIAL VOLTAGE-DEPENDENT ANION CHANNEL (VDAC) PROTEIN

摘要

Derivatives of geldanamycin (GA), a benzoquinone ansamycin antibiotic, are in clinical trials as anticancer drugs. While, at nanomolar concentrations, these drugs are known to target HSP90 chaperone activity, second anticancer activity that inhibits HGF/SF-mediated tumor cell invasion at nanomolar concentrations has been found. Disclosed is the identification of the outer membrane mitochondrial voltage-dependent anion channel (VDAC) protein, a component of the permeability transition pore (PTP), as a novel GA binding protein and a demonstration that GA inhibits membrane potential at picomolar levels. Uubiquinone 0 and decyl-ubiquinone, known benzoquinone inhibitors of mitochondrial PTP function like GA, inhibit HGF/SF induced urokinase (uPA) plasmin protease activation and HGF/SF activated membrane currents in whole-cell voltage clamp assays, with GA blocking at picomolar levels. The results disclosed regarding mechanism of action are a major step in harnessing such drugs for use for treating highly invasive cancers like glioblastoma.