HSPs (heat shock proteins) can be transiently synthesized when the cells exposure to heat or other stress, such as sodium arsenite, heavy metals, or amino acid analogues. Especially, a number of HSPs, including HSP40, HSP47, HSP70, HSP90, and HSP100 can be enhanced by heat shock and regulated at the transcriptional level in mammalian cells. KNK437 is an inhibitor of the acquisition of thermotolerance, which can inhibit various HSPs at the mRNA level transiently during the heat shock. Pre-treatment with 25-200μM KNK437 before the first heat treatment could dose-dependently inhibit the acquisition of thermotolerance of COLO 320DM or HeLa S3 cells by heat shock. Similarly, the inhibition of the acquisition of thermotolerance by 300μM sodium arsenite can be achieved by 100μM KNK437 pre-treatment in COLO 320DM cells. Addition of 100μM KNK437 during heat shock could specially inhibited the induction of major HSPs, including HSP110, HSP105, HSP72 and HSP40, but not the constitutively expressed HSP family proteins HSC73 or HSP90, in COLO 320DM. Treatment with KNK437 alone without heat shock did not show cytotoxicity[1]. Administration intraperitoneally of KNK473 at dose of 200mg/kg did not affect the tumor growth in mice, but dose at 6h prior to the first treatment can enhance the antitumor effects of fractionated heat treatment at 44°C in a synergistic manner, accompanied with inhibition of HSP72 observed in vivo[2].
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