دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | Subramanian C; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Grogan PT; Department of Internal Medicine, University of Wisconsin, Madison, WI, USA., Opipari VP; Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA., Timmermann BN; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA., Cohen MS; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. |
| المصدر: | Oncotarget [Oncotarget] 2018 Feb 07; Vol. 9 (18), pp. 14509-14523. Date of Electronic Publication: 2018 Feb 07 (Print Publication: 2018). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Impact Journals Country of Publication: United States NLM ID: 101532965 Publication Model: eCollection Cited Medium: Internet ISSN: 1949-2553 (Electronic) Linking ISSN: 19492553 NLM ISO Abbreviation: Oncotarget Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Albany, N.Y. : Impact Journals |
| مستخلص: | 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. Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest. |
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| معلومات مُعتمدة: | P20 RR015563 United States RR NCRR NIH HHS; P30 CA046592 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Akt/mToR/NFKB; N-myc; apoptosis; neuroblastoma; withanolides |
| تواريخ الأحداث: | Date Created: 20180328 Latest Revision: 20191120 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC5865686 |
| DOI: | 10.18632/oncotarget.24429 |
| PMID: | 29581860 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1949-2553 |
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| DOI: | 10.18632/oncotarget.24429 |