In a study reported in Cell, Kitambi and colleagues screened patient-derived glioblastoma cells to identify targetable cellular processes gained by these cells that are not necessarily involved in malignancy. They found that a quinine derivative (NSC13316) selectively compromised viability of glioblastoma cells.
Structure-activity relationships of the derivative were identified and exploited to produce analogs (vacquinols) with increased potency. The vacquinols were shown to induce death of glioblastoma cells via membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture.
Short hairpin RNA screening identified the MAP kinase MKK4 as a critical signaling node, with the kinase being required for vaquinol-induced vacuolization. In a glioblastoma multiforme animal model, vacquinol-1 had good pharmacokinetics and brain exposure and was associated with reduced disease progression and prolonged survival.
The investigators concluded, “These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.” ■
Kitambi SS, et al: Cell 157:313-328, 2014.