Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation
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We previously demonstrated that resveratrol and clofarabineelicited a marked cytotoxicity on malignant mesothelioma(MM) MSTO-211H cells but not on the corresponding normalmesothelial MeT-5A cells. Little is known of the possible moleculesthat could be used to predict preferential chemosensitivityon MSTO-211H cells. Resveratrol and clofarabineinduced down-regulation of Mcl-1 protein level in MSTO-211H cells. Treatment of cells with cycloheximide in the presenceof proteasome inhibitor MG132 suggested that Mcl-1protein levels were regulated at the post-translational step. ThesiRNA-based knockdown of Mcl-1 in MSTO-211H cells triggeredmore growth-inhibiting and apoptosis-inducing effectswith the resultant cleavages of procaspase-3 and its substratePARP, increased caspase-3/7 activity, and increased percentageof apoptotic propensities. However, the majority of the observedchanges were not shown in MeT-5A cells. Collectively,these studies indicate that the preferential activation of caspasecascade in malignant cells might have important applicationsas a therapeutic target for MM.
Abstract
We previously demonstrated that resveratrol and clofarabineelicited a marked cytotoxicity on malignant mesothelioma(MM) MSTO-211H cells but not on the corresponding normalmesothelial MeT-5A cells. Little is known of the possible moleculesthat could be used to predict preferential chemosensitivityon MSTO-211H cells. Resveratrol and clofarabineinduced down-regulation of Mcl-1 protein level in MSTO-211H cells. Treatment of cells with cycloheximide in the presenceof proteasome inhibitor MG132 suggested that Mcl-1protein levels were regulated at the post-translational step. ThesiRNA-based knockdown of Mcl-1 in MSTO-211H cells triggeredmore growth-inhibiting and apoptosis-inducing effectswith the resultant cleavages of procaspase-3 and its substratePARP, increased caspase-3/7 activity, and increased percentageof apoptotic propensities. However, the majority of the observedchanges were not shown in MeT-5A cells. Collectively,these studies indicate that the preferential activation of caspasecascade in malignant cells might have important applicationsas a therapeutic target for MM.
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