Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation.

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie
Thidarath RattanabureePotchanapond Graidist

Abstract

Kusunokinin, a lignan compound, inhibits cancer cell proliferation and induces apoptosis; however, the role of kusunokinin is not fully understood. Here, we aimed to identify a target protein of (-)-kusunokinin and determine the protein levels of its downstream molecules. We found that (-)-kusunokinin bound 5 possible target proteins, including CSF1R, MMP-12, HSP90-α, CyclinB1 and MEK1 with ΔGbind less than -10.40 kcal/mol. MD simulation indicated (-)-kusunokinin and pexidartinib (P31, a specific CSF1R binding compound) shared some extents of functional similarity in which (-)-kusunokinin bound CSF1R at the juxtamembrane (JM) region with aromatic amino acids similar to pexidartinib using π-π interaction, as well as hydrogen bond. Both P31 and (-)-kusunokinin moved into the same CSF1R region and W7 was a mutual key residue. However, the P31 binding site differed from the (-)-kusunokinin binding site. For in vitro study, the synthetic (±)-kusunokinin exhibited stronger cytotoxicity than picropodophyllotoxin, silibinin and etoposide on MCF-7 cells and represented less toxicity than picropodophyllotoxin and doxorubicin on L-929 and MCF-12A cells. Knocking down CSF1R using a specific siRNA combination with (±)-kusunokinin demonstrat...Continue Reading

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Citations

Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Thidarath RattanabureePotchanapond Graidist
Aug 28, 2021·International Journal of Molecular Sciences·Amber StillerBao-Hua Song
Jan 8, 2022·Oncology Letters·Nadeeya Mad-AdamPotchanapond Graidist

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