Perifosine-induced Inhibition of Akt Attenuates Brain-derived Neurotrophic Factor/TrkB-induced Chemoresistance in Neuroblastoma in Vivo

Overview

Journal Cancer

Publisher Wiley

Specialty Oncology

Date 2011 May 19

PMID 21590687

Citations 31

Authors

Zhijie Li

Doo-Yi Oh

Katsuya Nakamura

Carol J Thiele

Affiliations

Soon will be listed here.

Abstract

Background: Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB or activated Akt are associated with decreased event-free or overall survival in patients with NB. In the current study, the effect of perifosine, an Akt inhibitor, on the chemosensitivity of TrkB-expressing NB cells or tumors was evaluated.

Methods: A tetracycline-regulated TrkB-expressing isogenic NB cell model system was tested. In this system, NB cells were treated with etoposide and/or perifosine both in vitro and in vivo. Inhibition of the target by perifosine was evaluated by Western blot analysis or kinase activity assay. Cell survival and tumor growth were investigated.

Results: In vitro BDNF treatment induced Akt phosphorylation and rescued cells from etoposide-induced cell death in cells with high TrkB expression, but not in cells with low TrkB expression. Pretreatment of high TrkB-expressing TB3 cells with perifosine blocked BDNF/TrkB-induced Akt phosphorylation and inhibited BDNF's protection of TB3 cells from etoposide treatment. In vivo, tumors with high TrkB expression were found to have elevated levels of phosphorylated Akt and were less sensitive to etoposide treatment compared with tumors with low TrkB expression. Mice treated with a combination of perifosine and etoposide were found to have a statistically significant decrease in tumor growth compared with mice treated with either etoposide or perifosine alone. Activation of Akt through the BDNF/TrkB signaling pathway induced chemoresistance in NB in vivo.

Conclusions: Perifosine-induced inhibition of Akt increased the sensitivity of NB to chemotherapy. The results of the current study support the future clinical evaluation of an Akt inhibitor combined with cytotoxic drugs for the improvement of treatment efficacy.

Citing Articles

Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma.

Stauffer S, Roth J, Hernandez E, Kowalczyk J, Sealover N, Hebron K Cancers (Basel). 2024; 16(13).

PMID: 39001383 PMC: 11240493. DOI: 10.3390/cancers16132320.

Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase.

Cilenti L, Mahar R, Di Gregorio J, Ambivero C, Merritt M, Zervos A Front Cell Dev Biol. 2022; 10:904728.

PMID: 35846359 PMC: 9277447. DOI: 10.3389/fcell.2022.904728.

Interactions Among Brain-Derived Neurotrophic Factor and Neuroimmune Pathways Are Key Components of the Major Psychiatric Disorders.

Mehterov N, Minchev D, Gevezova M, Sarafian V, Maes M Mol Neurobiol. 2022; 59(8):4926-4952.

PMID: 35657457 DOI: 10.1007/s12035-022-02889-1.

Autophagy: a multifaceted player in the fate of sperm.

Wang M, Zeng L, Su P, Ma L, Zhang M, Zhang Y Hum Reprod Update. 2021; 28(2):200-231.

PMID: 34967891 PMC: 8889000. DOI: 10.1093/humupd/dmab043.

Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma.

Musumeci F, Cianciusi A, DAgostino I, Grossi G, Carbone A, Schenone S Molecules. 2021; 26(23).

PMID: 34885651 PMC: 8658969. DOI: 10.3390/molecules26237069.

References

Servidei T, Riccardi A, Sanguinetti M, Dominici C, Riccardi R . Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation. J Cell Physiol. 2006; 208(1):220-8. DOI: 10.1002/jcp.20659. View

Asgharzadeh S, Pique-Regi R, Sposto R, Wang H, Yang Y, Shimada H . Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst. 2006; 98(17):1193-203. DOI: 10.1093/jnci/djj330. View

George R, Sanda T, Hanna M, Frohling S, Luther 2nd W, Zhang J . Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008; 455(7215):975-8. PMC: 2587486. DOI: 10.1038/nature07397. View

Porta C, Figlin R . Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J Urol. 2009; 182(6):2569-77. DOI: 10.1016/j.juro.2009.08.085. View

Freireich E, Gehan E, Rall D, Schmidt L, Skipper H . Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep. 1966; 50(4):219-44. View

Brodeur G . Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003; 3(3):203-16. DOI: 10.1038/nrc1014. View

Li Z, Jaboin J, Dennis P, Thiele C . Genetic and pharmacologic identification of Akt as a mediator of brain-derived neurotrophic factor/TrkB rescue of neuroblastoma cells from chemotherapy-induced cell death. Cancer Res. 2005; 65(6):2070-5. DOI: 10.1158/0008-5472.CAN-04-3606. View

Brodeur G, Pritchard J, Berthold F, Carlsen N, Castel V, Castelberry R . Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993; 11(8):1466-77. DOI: 10.1200/JCO.1993.11.8.1466. View

Nakagawara A, Azar C, Scavarda N, Brodeur G . Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol. 1994; 14(1):759-67. PMC: 358424. DOI: 10.1128/mcb.14.1.759-767.1994. View

10.

Brodeur G . Getting into the AKT. J Natl Cancer Inst. 2010; 102(11):747-9. DOI: 10.1093/jnci/djq171. View

11.

Sagulenko V, Muth D, Sagulenko E, Paffhausen T, Schwab M, Westermann F . Cathepsin D protects human neuroblastoma cells from doxorubicin-induced cell death. Carcinogenesis. 2008; 29(10):1869-77. DOI: 10.1093/carcin/bgn147. View

12.

Nakagawara A, Scavarda N, Azar C, Cantor A, Brodeur G . Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med. 1993; 328(12):847-54. DOI: 10.1056/NEJM199303253281205. View

13.

Scala S, Wosikowski K, Giannakakou P, Valle P, Biedler J, Spengler B . Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity. Cancer Res. 1996; 56(16):3737-42. View

14.

Barnett S, Bilodeau M, Lindsley C . The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation. Curr Top Med Chem. 2005; 5(2):109-25. DOI: 10.2174/1568026053507714. View

15.

Matsumoto K, Wada R, Yamashiro J, Kaplan D, Thiele C . Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res. 1995; 55(8):1798-806. View

16.

Kim S, Hu W, Kelly D, Hellmich M, Evers B, Chung D . Gastrin-releasing peptide is a growth factor for human neuroblastomas. Ann Surg. 2002; 235(5):621-9; discussion 629-30. PMC: 1422487. DOI: 10.1097/00000658-200205000-00003. View

17.

Jaboin J, Kim C, Kaplan D, Thiele C . Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3'-kinase pathway. Cancer Res. 2002; 62(22):6756-63. View

18.

Opel D, Poremba C, Simon T, Debatin K, Fulda S . Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res. 2007; 67(2):735-45. DOI: 10.1158/0008-5472.CAN-06-2201. View

19.

Evans A, Kisselbach K, Liu X, Eggert A, Ikegaki N, Camoratto A . Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB. Med Pediatr Oncol. 2001; 36(1):181-4. DOI: 10.1002/1096-911X(20010101)36:1<181::AID-MPO1043>3.0.CO;2-Q. View

20.

Kumar A, Fillmore H, Kadian R, Broaddus W, Tye G, Van Meter T . The alkylphospholipid perifosine induces apoptosis and p21-mediated cell cycle arrest in medulloblastoma. Mol Cancer Res. 2009; 7(11):1813-21. DOI: 10.1158/1541-7786.MCR-09-0069. View