Hesperidin‐CAMKIV interaction and its impact on cell proliferation and apoptosis in the human hepatic carcinoma and neuroblastoma cells

Abstract

Calcium/calmodulin‐dependent protein kinase IV (CAMKIV) is a key regulatory molecule of cell signaling, and thereby controls its growth and proliferation, including expression of certain genes. The overexpression of CAMKIV is directly associated with the development of different types of cancers. Hesperidin is abundantly found in citrus fruits and exhibits wide range of pharmacological activities including anti‐inflammatory, antibacterial and anticancerous effects. We have investigated binding mechanism of hesperidin with the CAMKIV using molecular docking methods followed by fluorescence quenching and isothermal titration calorimetric assays. An appreciable binding affinity of hesperidin was observed with CAMKIV during fluorescence quenching and isothermal titration calorimetric studies. Efficacy of hesperidin to inhibit the growth of human hepatic carcinoma (HepG2) and neuroblastoma (SH‐SY5Y) cancer cell lines were investigated. Hesperidin has significantly reduced the proliferation of HepG2 and SH‐SY5Y cells and induces apoptosis by activating the caspase‐3‐dependent intrinsic pathway through the upregulation of proapoptotic Bax protein. Hesperidin treatment reduces the mitochondrial membrane potential of HepG2 and SH‐SY5Y cells. All these observations clearly anticipated hesperidin a potent inhibitor of CAMKIV which may be further exploited a newer therapeutic approach for the management of different cancer types.

Identification of Potential Inhibitors of Calcium/Calmodulin-Dependent Protein Kinase IV from Bioactive Phytoconstituents

“…CaMKIV possess an inherent ATPase activity [ 67 , 68 ]. Thus, we have employed BIOMOL reagent-based kinase assay wherein the inorganic phosphate released by the hydrolysis of ATP in a reaction catalyzed by CaMKIV forms a green-colored complex with malachite green.…”

Hesperidin ameliorates liver ischemia/reperfusion injury via activation of the Akt pathway

“…HDN also attenuated cerebral I/R injury through inhibiting the apoptotic pathway (47). However, studies have also reported that HDN induces apoptosis to reduce cancer cell prolif-eration (15,48). These differences may be due to the acute nature of I/R injury compared with the chronic induction of carcinoma.…”

Molecular mechanisms of action of hesperidin in cancer: Recent trends and advancements

“…A recent 25 evidence showed that Hesp is a potent inhibitor of calcium/calmodulin-dependent protein kinase IV (CAMKIV), and by inhibiting CAMKIV along with activating the caspase-3-dependent intrinsic pathway through the upregulation of pro-apoptotic protein, Bax (BCL2 associated X, apoptosis regulator), Hesp exerts its anti-apoptotic and anticancer activities. 27…”