Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth
Document Type
Article
Publication Title
Clinical Cancer Research
Abstract
Purpose: Classical pharmacology allows the use and development of conventional phytomedicine faster and more economically than conventional drugs. This approach should be tested for their efficacy in terms of complementarity and disease control. The purpose of this study was to determine the molecular mechanisms by which nimbolide, a triterpenoid found in the well-known medicinal plant Azadirachta indica, controls glioblastoma growth. Experimental Design: Using in vitro signaling, anchorage-independent growth, kinase assays, and xenograft models, we investigated the mechanisms of its growth inhibition in glioblastoma. Results: We show that nimbolide or an ethanol soluble fraction of A. indica leaves (Azt) that contains nimbolide as the principal cytotoxic agent is highly cytotoxic against glioblastoma multiforme in vitro and in vivo. Azt caused cell-cycle arrest, most prominently at the G1-S stage in glioblastoma multiforme cells expressing EGFRvIII, an oncogene present in about 20% to 25% of glioblastoma multiformes. Azt/nimbolide directly inhibited CDK4/CDK6 kinase activity leading to hypophosphorylation of the retinoblastoma protein, cell-cycle arrest at G1-S, and cell death. Independent of retinoblastoma hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of glioblastoma multiforme cells in vitro and in tumor xenografts by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, extracellular signal-regulated kinase 1/2, and STAT3. These effects were specific because Azt did not affect mTOR or other cell-cycle regulators. In vivo, Azt completely prevented initiation and inhibited progression of glioblastoma multiforme growth. Conclusions: Our preclinical findings demonstrate nimbolide as a potent anti-glioma agent that blocks cell cycle and inhibits glioma growth in vitro and in vivo. Clin Cancer Res; 20(1); 199-212. © 2013 AACR.
First Page
199
Last Page
212
DOI
10.1158/1078-0432.CCR-13-0762
Publication Date
1-1-2014
Recommended Citation
Karkare, Swagata; Chhipa, Rishi Raj; Anderson, Jane; Liu, Xiaona; Henry, Heather; Gasilina, Anjelika; Nassar, Nicholas; Roychoudhury, Jayeeta; Clark, Jason P.; Kumar, Ashish; Pauletti, Giovanni M.; Ghosh, Pradip K.; and Dasgupta, Biplab, "Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth" (2014). Pharmaceutical and Administrative Sciences Faculty Publications. 159.
https://doi.org/10.1158/1078-0432.CCR-13-0762
https://collections.uhsp.edu/pharm-admin-sciences_pubs/159