Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy

Mayank, .; Jaitak, Vikas

doi:10.1016/j.compbiolchem.2015.08.001

Cited by 34 publications

(15 citation statements)

References 69 publications

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“…Meanwhile, we observed that solasonine possessed selectivity against inhibiting Hh pathway activity, as supported by its minimal effect on the transcriptional activity provoked by PGE2 or TNF-α. Our data that solasonine is an Hh inhibitor by targeting Gli are consistent with the report from Mayank, who predicted solasonine as a Gli inhibitor by molecular docking method [17]. Solasonine is a major glycoalkaloid found in eggplant ( Solanum melongena ) and in a wide range of other Solanum species [18].…”

Section: Discussionsupporting

confidence: 90%

Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity

2016

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Abstract:The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1. However, we found that solasonine exhibited no effect on the transcriptional factors activities provoked by TNF-α and PGE2, thus suggesting its selectivity against Hh pathway activity. Furthermore, we identified that solasonine inhibited the Hh pathway activity by acting on its transcriptional factor Gli using a series of complementary data. We also observed that solasonine obviously inhibited the Gli-luciferase activity provoked by ectopic expression of Smo mutants which may cause the resistance to the current Smo inhibitors. Our study suggests that solasonine may significantly inhibit the Hh pathway activity by acting on Gli, therefore indicating the possibility to use solasonine as a lead compound to develop anticancer drugs for combating the resistance of current Smo inhibitors.

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Section: Discussionsupporting

confidence: 90%

Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity

2016

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“…Specifically, Visnyei et al identified emetine as an inhibitor of glioblastoma stem cells using a molecular screening system (27). Another study demonstrated that emetine inhibits the hedgehog signaling pathway by binding to hedgehog, smoothened and Gli protein, which have been implicated in the biology of cancer stem cells (CSCs) (28). However, the molecular mechanism by which emetine targets CSCs remains unclear, and such knowledge could facilitate the potential application of emetine and its structural modifications in cancer chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Emetine exhibits anticancer activity in breast cancer cells as an antagonist of Wnt/β‑catenin signaling

Sun

et al. 2019

Oncol Rep

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Emetine, an amoebicidal drug, exerts potent anticancer activity against various solid tumors, however, the underlying molecular mechanism remains unclear. In the present study, the effects of emetine were investigated on various proteins involved in the Wnt/β-catenin signaling pathway, which has been linked to various human cancers. It was revealed that emetine blocked Wnt/β-catenin signaling by targeting components of this pathway, including the low-density lipoprotein-receptor-related protein 6 (LRP6) and disheveled (DVL). Moreover, nanomolar concentrations of emetine decreased phosphorylation of these proteins and suppressed the expression of Wnt target genes, including fibronectin, frizzled-7 (Fzd7), c-Myc, Nanog and CD133 in MDA-MB-231 and MDA-MB-468 breast cancer cells. Additionally, emetine treatment induced apoptosis and suppressed the viability, migration, invasion, and sphere formation of breast cancer cells. Collectively the present results indicated that emetine antagonizes Wnt/β-catenin signaling, providing insight into the molecular mechanism underlying the anticancer activity of emetine.

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“…Thus, dual PARP and HDAC inhibitors, and P1/P2 represent promising lead compounds for further optimization to develop novel antitumor agents. Mayank and Jaitak (2016) investigated in silico the anticancer potential of alkaloids. Alkaloids are natural molecules that can be developed as multi-targeting inhibitors of the hedgehog (Hh) pathway.…”

Section: Cancermentioning

confidence: 99%

Drug discovery and computational strategies in the multitarget drugs era

Viana

Félix

Maia

et al. 2018

Braz. J. Pharm. Sci.

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The pharmaceutical industry is increasingly joining chemoinformatics in the search for the development of new drugs to be used in the treatment of diseases. These computational studies have the advantage of being less expensive and optimize the study time, and thus the interest in this area is increasing. Among the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due to the improvement in the quality of treatment involving several drugs. Multitarget therapy is more effective than traditional drug therapy that emphasizes maximum selectivity for a single target. In this review a multitarget drug survey was carried out as a promising strategy in several important diseases: neglected diseases, neurodegenerative diseases, AIDS, and cancer. In addition, we discuss Computer-Aided Drug Design (CADD) techniques as a tool in the projection of multitarget compounds against these diseases.

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Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy

Cited by 34 publications

References 69 publications

Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity

Solasonine, A Natural Glycoalkaloid Compound, Inhibits Gli-Mediated Transcriptional Activity

Emetine exhibits anticancer activity in breast cancer cells as an antagonist of Wnt/β‑catenin signaling

Drug discovery and computational strategies in the multitarget drugs era

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