By way of x-ray crystallography and kinase-inhibitor specificity profiling, College of California San Diego Faculty of Drugs researchers, in collaboration with researchers at Peking College and Zhejiang College, reveal that curcumin, a pure occurring chemical compound discovered within the spice turmeric, binds to the kinase enzyme dual-specificity tyrosine-regulated kinase 2 (DYRK2) on the atomic degree. This beforehand unreported biochemical interplay of curcumin results in inhibition of DYRK2 that impairs cell proliferation and reduces most cancers burden.
However earlier than turning to curcumin or turmeric dietary supplements, Sourav Banerjee, PhD, UC San Diego Faculty of Drugs postdoctoral scholar, cautions that curcumin alone might not be the reply.
“Typically, curcumin is expelled from the physique fairly quick,” stated Banerjee. “For curcumin to be an efficient drug, it must be modified to enter the blood stream and keep within the physique lengthy sufficient to focus on the most cancers. Owing to numerous chemical drawbacks, curcumin by itself might not be enough to utterly reverse most cancers in human sufferers.”
Writing within the July 9 difficulty of the Proceedings of the Nationwide Academy of Sciences, Banerjee and colleagues report that curcumin binds to and inhibits DYRK2 resulting in the obstacle of the proteasome — the mobile protein equipment that destroys unneeded or broken proteins in cells — which in flip reduces most cancers in mice.
“Though curcumin has been studied for greater than 250 years and its anti-cancer properties have been beforehand reported, no different group has reported a co-crystal construction of curcumin certain to a protein kinase goal till now,” stated Banerjee, first writer on the research. “Due to their work on the crystallography, our collaborators at Peking College, Chenggong Ji and Junyu Xiao, helped us to visualise the interplay between curcumin and DYRK2.”
“The enzyme kinases IKK and GSK3 have been regarded as the prime curcumin-targets that result in anti-cancer impact however the co-crystal construction of curcumin with DYRK2 together with a 140-panel kinase inhibitor profiling reveal that curcumin binds strongly to the lively website of DYRK2, inhibiting it at a degree that’s 500 instances stronger than IKK or GSK3.”
Working alongside Jack E. Dixon, PhD, Distinguished Professor of Pharmacology, Mobile and Molecular Drugs, Chemistry and Biochemistry at UC San Diego, Banerjee and group have been in search of regulators of proteasomes to inhibit tumor formation by proteasome-addicted cancers like triple-negative breast most cancers (TNBC) and the plasma cell malignancy referred to as a number of myeloma.
Utilizing biochemical, mouse most cancers fashions and mobile fashions the group discovered that curcumin is a selective inhibitor of DYRK2 and that this novel molecular goal has promising anticancer potential for not solely chemo-sensitive but in addition proteasome inhibitor resistant/tailored cancers.
“Our outcomes reveal an sudden position of curcumin in DYRK2-proteasome inhibition and supply a proof-of-concept that pharmacological manipulation of proteasome regulators could provide new alternatives for hard-to-treat triple-negative breast most cancers and a number of myeloma therapy,” stated Dixon, who was co-senior writer with Zhejiang College’s Xing Guo, PhD, on the paper. “Our main focus is to develop a chemical compound that may goal DYRK2 in sufferers with these cancers.”
DYRK2 depletion impairs proteasome exercise and displays slower most cancers proliferation charges and considerably decreased tumor burden in mouse fashions. Together with the FDA-approved a number of myeloma drug, carfilzomib, curcumin induced a a lot increased most cancers cell dying whereas regular non-cancerous cells have been much less affected. This recommend that focusing on proteasome regulators (reminiscent of DYRK2) together with proteasome inhibitors could also be a promising method of anticancer remedy with much less side-effects however additional work is required, stated Banerjee.
Co-authors embrace: Joshua E. Mayfield, UC San Diego and Apollina Goel, College of Iowa.
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