C0818, a novel curcumin derivative, interacts with Hsp90 and inhibits Hsp90 ATPase activity
نویسندگان
چکیده
The aims of the present study were to estimate the affinity between 3,5-(E)-bis(3-methoxy-4-hydroxybenzal)-4-piperidinone hydrochloride (C0818) and heat shock protein 90 (Hsp90) and to investigate the inhibitory effects of this compound on Hsp90 ATPase activity. Fluorescence spectroscopy was used to examine the affinity between varying concentrations of C0818 and Hsp90, N-Hsp90, M-Hsp90 and C-Hsp90. Fluorescence intensities were recorded in the range of 290-510 nm at 293, 303 and 310 K, respectively. A colorimetric assay for inorganic phosphate (based on the formation of a phosphomolybdate complex and the subsequent reaction with malachite green) were used to examine the inhibitory effects of C0818 on Hsp90 ATPase activity. The equilibrium dissociation constant KD value of C0818 was found to be 23.412±0.943 μmol/L. The interaction between C0818 and Hsp90 was driven mainly by electrostatic interactions. C0818 showed the strongest affinity with C-Hsp90. These results conclusively demonstrate the inhibitory activity of C0818 on the activity of Hsp90 ATPase.
منابع مشابه
Dual inhibition of Bcr-Abl and Hsp90 by C086 potently inhibits the proliferation of imatinib-resistant CML cells.
PURPOSE Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and LS...
متن کاملCancer Therapy: Preclinical Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells
Purpose: Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and L...
متن کاملY‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo
Heat shock protein 90 (Hsp90) stabilizes a variety of proteins required for cancer cell survival and has been identified as a promising drug target for cancer treatment. To date, several Hsp90 inhibitors have entered into clinical trials, but none has been approved for cancer therapy yet. Thus, exploring new Hsp90 inhibitors with novel mechanisms of action is urgent. In the present study, we sh...
متن کاملCdc37-Hsp90 complexes are responsive to nucleotide-induced conformational changes and binding of further cofactors.
Hsp90 is an ATP-dependent molecular chaperone, which facilitates the activation and stabilization of hundreds of client proteins in cooperation with a defined set of cofactors. Many client proteins are protein kinases, which are activated and stabilized by Hsp90 in cooperation with the kinase-specific co-chaperone Cdc37. Other Hsp90 co-chaperones, like the ATPase activator Aha1, also are implic...
متن کاملStimulation of the weak ATPase activity of human hsp90 by a client protein.
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the folding and assembly of a limited set of "client" proteins, many of which are involved in signal transduction pathways. In vivo, it is found in complex with additional proteins, including the chaperones Hsp70, Hsp40, Hip and Hop (Hsp-interacting and Hsp-organising proteins, respectively), as well as high molecular mass immun...
متن کامل