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Benzylidene Lactam Compound, KNK437, a Novel Inhibitor of Acquisition of Thermotolerance and Heat Shock Protein Induction in Human Colon Carcinoma Cells

Takasago Research Laboratories, Research Institute, Kaneka Corporation, Takasago 676-8688, Japan [S. Y., M. K.], and Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan [K. N.]

Cells exposed to heat or other types of stressors transiently synthesize a group of proteins known as heat shock proteins (HSPs). A nonlethal heat treatment can elicit in the cells an ability to resist subsequent lethal heat treatments. We report here that a novel benzylidene lactam compound, KNK437, dose-dependently inhibited the acquisition of thermotolerance and the induction of various HSPs including HSP105, HSP70, and HSP40 in COLO 320DM (human colon carcinoma) cells. The induction of heat-inducible HSP70, which is reported to be involved in the development of thermotolerance, was inhibited at mRNA levels by treatment with KNK437. This compound also inhibited the acquisition of thermotolerance as developed by sodium arsenite. However, it did not increase thermosensitivity in nontolerant cells. The effect of KNK437 was much greater than that of quercetin, a bioflavonoid that was previously reported to inhibit the acquisition of thermotolerance as well as the induction of HSPs. We conclude that this drug is a novel inhibitor of the acquisition of thermotolerance caused by the induction of HSPs.

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