TY - JOUR
T1 - Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1
T2 - A Chemopreventive Role in Lung Cancer
AU - Roy, Sonam
AU - Mohammad, Taj
AU - Gupta, Preeti
AU - Dahiya, Rashmi
AU - Parveen, Shahnaz
AU - Luqman, Suaib
AU - Hasan, Gulam Mustafa
AU - Hassan, Md Imtaiyaz
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.
AB - The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.
UR - http://www.scopus.com/inward/record.url?scp=85091023949&partnerID=8YFLogxK
U2 - 10.1021/acsomega.0c02165
DO - 10.1021/acsomega.0c02165
M3 - Article
AN - SCOPUS:85091023949
SN - 2470-1343
VL - 5
SP - 21550
EP - 21560
JO - ACS Omega
JF - ACS Omega
IS - 34
ER -
