The quinolinone derivative vesnarinone potentiates the cytotoxicity of doxorubicin in HL-60 leukemia cells

Vesnarinone, (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone), a quinolinone derivative, is a positive inotropic agent. We examined the cytotoxicity either by vesnarinone alone or in combination with doxorubicin (DXR), in vitro. The cytotoxic effect of vesnarinone against HL-60 cells did not increase, even at concentrations as high as (50 μg/ml). The cytotoxicity of DXR, however, was enhanced after being combined with 30 μg/ml of vesnarinone. The intracellular level of DXR increased when DXR was administered after incubation with vesnarinone and the efflux of DXR was delayed when the cells were incubated in the presence of vesnarinone after DXR exposure. Flow cytometry showed that the combination of DXR and vesnarinone increased the cell population below the G₀/G₁ region. Vesnarinone induced DNA ladder formation, but only when these cells were incubated for 72 h, while in addition, when DXR was combined with vesnarinone, the DNA ladder formation was enhanced. Based on the above findings, we thus conclude that the cytotoxicity of DXR was enhanced when combined with vesnarinone.