Vacquinol-1 is a small molecule that kills glioblastoma cells by causing extreme vacuolization.

  • Major finding: Vacquinol-1 is a small molecule that kills glioblastoma cells by causing extreme vacuolization.

  • Concept: Vacquinol-1 induces membrane ruffling and massive macropinocytosis that eventually ruptures cells.

  • Impact: Compounds that induce catastrophic vacuolization in cancer cells may be therapeutically effective.

The genomic complexity and diversity of glioblastoma multiforme (GBM), a highly malignant and currently incurable form of brain cancer, have hindered efforts to develop targeted therapies. Hypothesizing that GBM may acquire unique alterations to cellular functions not directly involved in cell growth or transformation that could be exploited for the development of novel therapeutic approaches, Kitambi and colleagues tested a library of compounds for their ability to selectively retard the growth of patient-derived GBM cell lines. Candidate compounds were evaluated for in vivo toxicity and efficacy in a zebrafish GBM model. The most potent compound, dubbed “Vacquinol-1” because of its quinolone-alcohol scaffold, rapidly induced ATP loss and GBM cell death, but not through apoptotic or autophagic mechanisms. Instead, Vacquinol-1 induced cell rounding, membrane ruffling, and widespread macropinocytosis, or fluid internalization, that subsequently led to massive vacuolization, cell rupture, and necrotic-like cell death. A short hairpin RNA screen revealed that Vacquinol-1–induced cell death was dependent on activation of MAP kinase kinase 4 (MKK4), though the mechanism of MKK4 activation and the role of MKK4 in vacuolization remain unclear. Preclinical profiling of Vacquinol-1 predicted high membrane permeability and metabolic stability in liver cells; accordingly, the compound showed rapid in vivo tissue dispersal, high stability, and low plasma clearance in mice, raising the possibility that Vacquinol-1 could be used in treatment of GBM. Indeed, Vacquinol-1 strongly inhibited growth of patient-derived GBM xenografts in zebrafish, and orally administered Vacquinol-1 dramatically attenuated tumor growth and prolonged survival in tumor-bearing mice that had been intracranially injected with patient-derived GBM cell lines. Together, these data suggest that GBM cells are distinguished by their sensitivity to excessive vacuolization, and that targeting this vulnerability with compounds such as Vacquinol-1 may have clinical benefit.

Kitambi SS, Toledo EM, Usoskin D, Wee S, Harisankar A, Svensson R, et al. Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. Cell 2014;157:313–28.

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