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

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.

Retracted : Salidroside from Rhodiola wallichiana var. cholaensis reverses insulin resistance and stimulates the GLP‐1 secretion by alleviating ROS‐mediated activation of MAPKs signaling pathway and mitigating apoptosis

“…The mTOR signaling pathway is generally known as an important regulator in cytoskeletal formation, protein synthesis, cell proliferation, growth, and apoptosis by regulating the downstream target the level of p70S6k in mammalian cells (Guo et al, 2015). Subramanian and his team found that the mTOR signaling pathway was inhibited in oxidative stress, thereby inducing apoptosis (Subramanian, Grogan, Opipari, Timmermann, & Cohen, 2018). Besides, GLUTag cells treated with H 2 O 2 had been shown that ROS production was associated with the inhibition of mTOR signaling pathways (Green, Vasu, & Flatt, 2016).…”

Molecular targeting therapies for neuroblastoma: Progress and challenges

“…Research conducted by Kunnimalaiyaan et al 168 has demonstrated that LY2090314 (a GSK‐3 inhibitor) is capable for causing growth inhibition and inducing apoptosis in NB cells, and also reducing the survivin level. Withanolides (WA, WGA, WGB‐DA, WGA‐TA) have also been found to be cytotoxic to NB cells, potentially because they downregulate survivin in NB cells 169 . Noscapine, a nontoxic natural compound, induces apoptosis via downregulation of survivin in both p53 wild type and null NB cells 170 .…”

Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model

“…NF-κB is a well-known target for withanolides, and its inhibition was investigated to further assess what was the role of this pathway in the antiproliferative activity observed for the withanolides included in this SAR. 41,42 Compounds that displayed an antiproliferative activity (IC 50 < 500 nM in RPMI 8226), as well as other analogues important to study SAR, were tested for their NF-κB inhibition (Table 3). Most compounds displayed a better activity than parthenolide, the positive control.…”