Oncotarget

Research Papers:

Novel natural withanolides induce apoptosis and inhibit migration of neuroblastoma cells through down regulation of N-myc and suppression of Akt/mTOR/NF-κB activation

Chitra Subramanian _, Patrick T. Grogan, Valerie P. Opipari, Barbara N. Timmermann and Mark S. Cohen

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Oncotarget. 2018; 9:14509-14523. https://doi.org/10.18632/oncotarget.24429

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Abstract

Chitra Subramanian1, Patrick T. Grogan2, Valerie P. Opipari3, Barbara N. Timmermann4 and Mark S. Cohen1,5

1Department of Surgery, University of Michigan, Ann Arbor, MI, USA

2Department of Internal Medicine, University of Wisconsin, Madison, WI, USA

3Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

4Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA

5Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

Correspondence to:

Mark S. Cohen, email: [email protected]

Keywords: neuroblastoma; withanolides; N-myc; Akt/mToR/NFKB; apoptosis

Received: December 15, 2016     Accepted: September 04, 2017     Epub: February 07, 2018     Published: March 06, 2018

ABSTRACT

Despite recent advances in intensive chemotherapy treatments, long-term success is achieved in less than 30% of children with high-risk neuroblastoma (NB). Key regulatory pathways including the PI3K/Akt, mTOR and NF-κB are implicated in the pathogenesis of NB. Although drugs targeting these individual pathways are in clinical trials, they are not effective due to the activation of compensatory mechanisms. We have previously reported that natural novel withanolides from Physalis longifolia can potently inhibit these key regulatory pathways simultaneously. In the present study, we examined the efficacy and mechanisms through which novel withanolides and their acetate derivatives (WGA-TA and WGB-DA) from P.longifolia kill NB cells. The results from the study demonstrated that our novel acetate derivatives are highly effective in inhibiting the proliferation, shifting the cell cycle and inducing apoptosis in a dose dependent manner. Analysis of oncogenic pathway proteins targeted by withanolides indicated induction of heat shock response due to oxidative stress. Dose dependent decrease in clients of HSP90 chaperone function due to suppression of Akt, mTOR, and NF-κB pathways led to decrease in the expressions of target genes such as cyclin D1, N-myc and Survivin. Additionally, there was a dose dependent attenuation of the migration and invasion of NB cells. Furthermore, the lead compound WGA-TA showed significant reduction in tumor growth of NB xenografts. Taken together, these results suggest that withanolides are an effective therapeutic option against NBs.


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