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,Mark S Cohen,Valerie P Opipari,Barbara N Timmermann,Patrick T Grogan

doi:10.18632/oncotarget.24429

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.

Highlights

Neuroblastoma (NB) is an aggressive neural crest derived pediatric malignancy accounting for 8–10% of all pediatric cancers and is often refractory to conventional therapies [1, 2]
We have previously reported that natural novel withanolides from Physalis longifolia can potently inhibit these key regulatory pathways simultaneously
In addition to the standard treatment options, targeted therapies using inhibitors of molecules implicated in the pathogenesis of NB such as anaplastic lymphoma kinase (ALK), tropomyosin receptor kinase (TRK), the phosphatidylinositol 3′-kinase (PI3K)/Akt/mammalian target of rapamycin and the insulin-like growth factor 1 receptor (IGF1R), histone deacetylases (HDAC) and others are in phase I/II clinical trials either alone or in combination [5,6,7,8,9,10] to improve the outcome of highrisk NB patients

Summary

Introduction

Neuroblastoma (NB) is an aggressive neural crest derived pediatric malignancy accounting for 8–10% of all pediatric cancers and is often refractory to conventional therapies [1, 2]. Despite intense multimodal therapy and improvements in understanding the molecular and genetic basis of NB, the therapeutic outcome of high risk children have a dismal long-term survival rate of only 18–30% either due to recurrence after treatment or due to the development of resistance to conventional therapy [3]. In addition to the standard treatment options, targeted therapies using inhibitors of molecules implicated in the pathogenesis of NB such as anaplastic lymphoma kinase (ALK), tropomyosin receptor kinase (TRK), the phosphatidylinositol 3′-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the insulin-like growth factor 1 receptor (IGF1R), histone deacetylases (HDAC) and others are in phase I/II clinical trials either alone or in combination [5,6,7,8,9,10] to improve the outcome of highrisk NB patients. Development of drugs targeting multiple pathways implicated in the pathogenesis of NB and has lower toxicity profiles are urgently needed

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Conclusion