Honokiol triggers receptor‑interacting protein kinase 3‑mediated cell death of neuroblastoma cells by upregulating reactive oxygen species

Zhang,Jiao; Liu,Qiuliang; Shi,Longyan; Qin,Pan; Wang,Qi

doi:10.3892/mmr.2017.7628

Honokiol triggers receptor‑interacting protein kinase 3‑mediated cell death of neuroblastoma cells by upregulating reactive oxygen species

Authors:
- Jiao Zhang
- Qiuliang Liu
- Longyan Shi
- Pan Qin
- Qi Wang
View Affiliations

Affiliations: Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: September 26, 2017 https://doi.org/10.3892/mmr.2017.7628
Pages: 8525-8529

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Neuroblastoma is the most common form of childhood extracranial tumor and almost half of neuroblastoma cases occur in infants under two years old. Neuroblastoma accounts for ~6‑10% of childhood cancers and 15% of cancer‑associated childhood mortality. However, an effective treatment remains to be developed. Honokiol exhibits long‑lasting central muscle relaxation, anti‑inflammatory, antibacterial, antimicrobial, antiulcer, antioxidation, antiaging and antitumor effects. Honokiol has been previously demonstrated to kill neuroblastoma cells, however, the underlying mechanism of action remains unclear. The present study reports that honokiol inhibits the growth of neuroblastoma cells via upregulation of reactive oxygen species (ROS). MTT assays demonstrated that treatment of Neuro‑2a neuroblastoma cells with honokiol resulted in time‑ and dose‑dependent inhibition of cell proliferation, which was associated with upregulation of the protein expression of receptor‑interacting protein kinase 3 (RIP3), as demonstrated by western blot analysis. Furthermore, knockdown of RIP3 by small interfering RNA, or pharmacological inhibition of RIP3 by the RIP3 specific inhibitor necrosulfonamide, reversed honokiol‑induced loss of cell viability in Neuro‑2a cells. Importantly, honokiol significantly increased the intracellular ROS levels as determined by a 2',7'‑dichlorofluorescin diacetate assay, while ROS scavenger N‑acetyl cysteine significantly prevented the induction of ROS and RIP3 by honokiol. The results of the present study indicate that honokiol may suppress the growth of neuroblastoma Neuro‑2a cells, at least partially, through ROS‑mediated upregulation of RIP3.

View Figures

View References

1	Hoehner JC, Gestblom C, Hedborg F, Sandstedt B, Olsen L and Påhlman S: A developmental model of neuroblastoma: Differentiating stroma-poor tumors' progress along an extra-adrenal chromaffin lineage. Lab Invest. 75:659–675. 1996.PubMed/NCBI
2	Spix C, Pastore G, Sankila R, Stiller CA and Steliarova-Foucher E: Neuroblastoma incidence and survival in European children (1978–1997): Report from the automated childhood cancer information system project. Eur J Cancer. 42:2081–2091. 2006. View Article : Google Scholar : PubMed/NCBI
3	Izbicki T, Mazur J and Izbicka E: Epidemiology and etiology of neuroblastoma: An overview. Anticancer Res. 23:755–760. 2003.PubMed/NCBI
4	Maris JM: Recent advances in neuroblastoma. N Engl J Med. 362:2202–2211. 2010. View Article : Google Scholar : PubMed/NCBI
5	Maris JM, Hogarty MD, Bagatell R and Cohn SL: Neuroblastoma. Lancet. 369:2106–2120. 2007. View Article : Google Scholar : PubMed/NCBI
6	De Bernardi B, Mosseri V, Rubie H, Castel V, Foot A, Ladenstein R, Laureys G, Beck-Popovic M, de Lacerda AF, Pearson AD, et al: Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group. Br J Cancer. 99:1027–1033. 2008. View Article : Google Scholar : PubMed/NCBI
7	Zage PE, Kletzel M, Murray K, Marcus R, Castleberry R, Zhang Y, London WB and Kretschmar C; Children's Oncology Group, : Outcomes of the POG 9340/9341/9342 trials for children with high-risk neuroblastoma: A report from the children's oncology group. Pediatr Blood Cancer. 51:747–753. 2008. View Article : Google Scholar : PubMed/NCBI
8	Hoy SM: Dinutuximab: A review in high-risk neuroblastoma. Target Oncol. 11:247–253. 2016. View Article : Google Scholar : PubMed/NCBI
9	Bai X, Cerimele F, Ushio-Fukai M, Waqas M, Campbell PM, Govindarajan B, Der CJ, Battle T, Frank DA, Ye K, et al: Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem. 278:35501–35507. 2003. View Article : Google Scholar : PubMed/NCBI
10	Chen XR, Lu R, Dan HX, Liao G, Zhou M, Li XY and Ji N: Honokiol: A promising small molecular weight natural agent for the growth inhibition of oral squamous cell carcinoma cells. Int J Oral Sci. 3:34–42. 2011. View Article : Google Scholar : PubMed/NCBI
11	Wang X, Duan X, Yang G, Zhang X, Deng L, Zheng H, Deng C, Wen J, Wang N, Peng C, et al: Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One. 6:e184902011. View Article : Google Scholar : PubMed/NCBI
12	Shigemura K, Arbiser JL, Sun SY, Zayzafoon M, Johnstone PA, Fujisawa M, Gotoh A, Weksler B, Zhau HE and Chung LW: Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer. 109:1279–1289. 2007. View Article : Google Scholar : PubMed/NCBI
13	Prasad R, Kappes JC and Katiyar SK: Inhibition of NADPH oxidase 1 activity and blocking the binding of cytosolic and membrane-bound proteins by honokiol inhibit migratory potential of melanoma cells. Oncotarget. 7:7899–7912. 2016. View Article : Google Scholar : PubMed/NCBI
14	Lin JW, Chen JT, Hong CY, Lin YL, Wang KT, Yao CJ, Lai GM and Chen RM: Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway. Neuro Oncol. 14:302–314. 2012. View Article : Google Scholar : PubMed/NCBI
15	Proskuryakov SY, Konoplyannikov AG and Gabai VL: Necrosis: A specific form of programmed cell death? Exp Cell Res. 283:1–16. 2003. View Article : Google Scholar : PubMed/NCBI
16	Moriwaki K and Chan FK: RIP3: A molecular switch for necrosis and inflammation. Genes Dev. 27:1640–1649. 2013. View Article : Google Scholar : PubMed/NCBI
17	Cai R, Xue W, Liu S, Petersen RB, Huang K and Zheng L: Overexpression of glyceraldehyde 3-phosphate dehydrogenase prevents neurovascular degeneration after retinal injury. FASEB J. 29:2749–2758. 2015. View Article : Google Scholar : PubMed/NCBI
18	Lin CJ, Chang YA, Lin YL, Liu SH, Chang CK and Chen RM: Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis. Phytomedicine. 23:517–527. 2016. View Article : Google Scholar : PubMed/NCBI
19	Lin CJ, Chen TL, Tseng YY, Wu GJ, Hsieh MH, Lin YW and Chen RM: Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway. Toxicol Appl Pharmacol. 304:59–69. 2016. View Article : Google Scholar : PubMed/NCBI
20	Hahm ER, Sakao K and Singh SV: Honokiol activates reactive oxygen species-mediated cytoprotective autophagy in human prostate cancer cells. Prostate. 74:1209–1221. 2014. View Article : Google Scholar : PubMed/NCBI
21	Zhang M, Harashima N, Moritani T, Huang W and Harada M: The roles of ROS and caspases in TRAIL-induced apoptosis and necroptosis in human pancreatic cancer cells. PLoS One. 10:e01273862015. View Article : Google Scholar : PubMed/NCBI