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. 2015 Jul 13:2:984-989.
doi: 10.1016/j.toxrep.2015.07.004. eCollection 2015.

Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells

Ji Yeon Lim  1   2 , Joo Yun Lee  3 , Byung Jin Byun  3 , Seong Hwan Kim  1   2
Affiliations

Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells

Ji Yeon Lim et al. Toxicol Rep. .

Abstract

Aberrant regulation of phosphatidylinositol-3-kinases (PI3Ks) is known to be involved in the progression of cancers. PI3K-binding flavonoids such as quercetin and myricetin have been shown to inhibit PI3K activity, but the direct targeting of fisetin to PI3K has not been established. Here, we carried out an in silico investigation of fisetin binding to PI3K and determined fisetin's inhibitory activity in enzymatic and cell-based assays. In addition, fisetin induced apoptosis in human Burkitt's lymphoma Raji cells by inhibiting both PI3Ks and mammalian target of rapamycin (mTOR). Our results indicate that fisetin may serve as a natural backbone for the development of novel dual inhibitors of PI3Ks and mTOR for the treatment of cancer.

Keywords: Apoptosis; Burkitt’s lymphoma; Fisetin; Fisetin (CID: 5281614); PI3K; mTOR.

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Figures

Fig. 1
Fig. 1
Fisetin targets and inhibits PI3K activity. (A) Chemical structure of fisetin. (B) Proposed binding mode of fisetin (green) to the ATP-binding pocket of PI3K. PI3K and interacting residues are represented by ribbons and sticks, respectively. Hydrogen-bonding interactions appear as dashed yellow lines; all hydrogen atoms except those involved in hydrogen bonding were omitted for clarity. (C) Assay of PI3K kinase activity in the presence of fisetin (Materials and methods). *P < 0.05; **P < 0.01; ***P < 0.001. (D) Immunoblotting assay of PI3K activity (Materials and methods).
Fig. 2
Fig. 2
Fisetin induces apoptosis in Raji cells. (A) Effect of fisetin on the viability of Raji cells (Materials and Methods). *P < 0.05; **P < 0.01; ***P < 0.001. (B) Flow cytometry to determine the number of apoptosis cells stained with Annexin V and propidium iodide relative to the total number of cells analyzed. (C) Immunoblotting of the effect of fisetin on the expression levels of apoptosis-related proteins.
Fig. 3
Fig. 3
Fisetin inhibits mTOR activity and induces DNA damage. Immunoblotting of the effects of fisetin on the expression levels of proteins related to mTOR signaling and DNA damage.
See this image and copyright information in PMC

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