Honokiol Traverses the Blood-brain Barrier and Induces Apoptosis of Neuroblastoma Cells Via an Intrinsic Bax-mitochondrion-cytochrome C-caspase Protease Pathway

Overview

Journal Neuro Oncol

Publisher Oxford University Press

Specialties Neurology
Oncology

Date 2012 Jan 20

PMID 22259050

Citations 52

Authors

Jia-Wei Lin

Juei-Tai Chen

Chung-Ye Hong

Yi-Ling Lin

Kuan-Ting Wang

Chih-Jung Yao

Gi-Ming Lai

Ruei-Ming Chen

Affiliations

Soon will be listed here.

Abstract

Neuroblastomas, an embryonic cancer of the sympathetic nervous system, often occur in young children. Honokiol, a small-molecule polyphenol, has multiple therapeutic effects and pharmacological activities. This study was designed to evaluate whether honokiol could pass through the blood-brain barrier (BBB) and induce death of neuroblastoma cells and its possible mechanisms. Primary cerebral endothelial cells (CECs) prepared from mouse brain capillaries were cultured at a high density for 4 days, and these cells formed compact morphologies and expressed the ZO-1 tight-junction protein. A permeability assay showed that the CEC-constructed barrier obstructed the passing of FITC-dextran. Analyses by high-performance liquid chromatography and the UV spectrum revealed that honokiol could traverse the CEC-built junction barrier and the BBB of ICR mice. Exposure of neuroblastoma neuro-2a cells and NB41A3 cells to honokiolinduced cell shrinkage and decreased cell viability. In parallel, honokiol selectively induced DNA fragmentation and cell apoptosis rather than cell necrosis. Sequential treatment of neuro-2a cells with honokiol increased the expression of the proapoptotic Bax protein and its translocation from the cytoplasm to mitochondria. Honokiol successively decreased the mitochondrial membrane potential but increased the release of cytochrome c from mitochondria. Consequently, honokiol induced cascade activation of caspases-9, -3, and -6. In comparison, reducing caspase-6 activity by Z-VEID-FMK, an inhibitor of caspase-6, simultaneously attenuated honokiol-induced DNA fragmentation and cell apoptosis. Taken together, this study showed that honokiol can pass through the BBB and induce apoptotic insults to neuroblastoma cells through a Bax-mitochondrion-cytochrome c-caspase protease pathway. Therefore, honokiol may be a potential candidate drug for treating brain tumors.

Citing Articles

Inhibition of amyloid β aggregation and BACE1, and protective effect on SH-SY5Y cells, by p-terphenyl compounds from mushroom Thelephora aurantiotincta.

Hirabayashi S, Fujihara K, Saito T, Sasaki H, Koike S, Ogasawara Y J Nat Med. 2024; 79(1):268-277.

PMID: 39612118 DOI: 10.1007/s11418-024-01865-4.

Hearing loss during chemotherapy: prevalence, mechanisms, and protection.

Kessler L, Koo C, Richter C, Tan X Am J Cancer Res. 2024; 14(9):4597-4632.

PMID: 39417180 PMC: 11477841. DOI: 10.62347/OKGQ4382.

Honokiol relieves hippocampal neuronal damage in Alzheimer's disease by activating the SIRT3-mediated mitochondrial autophagy.

Li H, Sun J, Wu Y, Yang Y, Zhang W, Tian Y CNS Neurosci Ther. 2024; 30(8):e14878.

PMID: 39097923 PMC: 11298204. DOI: 10.1111/cns.14878.

Effect of Honokiol on culture time and survival of Alzheimer's disease iPSC-derived neurons.

Thuy Le D, Vu C, Ly T, Nguyen N, Nguyen P, Chu H Bioimpacts. 2024; 14(1):27652.

PMID: 38327632 PMC: 10844589. DOI: 10.34172/bi.2023.27652.

Stem Extract and Nanoparticles: Effects on Proliferation, Colony Formation, Apoptosis Induction, Cell Cycle Arrest, and Mitochondrial Membrane Potential in Human Breast Adenocarcinoma Breast Cancer Cells.

Chittasupho C, Samee W, Takuathung M, Okonogi S, Nimkulrat S, Athikomkulchai S Int J Mol Sci. 2024; 25(2).

PMID: 38256052 PMC: 10815711. DOI: 10.3390/ijms25020978.

References

Tang W, Wan M, Zhu Z, Chen G, Huang X . Simultaneous determination of eight major bioactive compounds in Dachengqi Tang (DT) by high-performance liquid chromatography. Chin Med. 2008; 3:5. PMC: 2383911. DOI: 10.1186/1749-8546-3-5. View

van der Pal H, van Dalen E, Kremer L, Bakker P, van Leeuwen F . Risk of morbidity and mortality from cardiovascular disease following radiotherapy for childhood cancer: a systematic review. Cancer Treat Rev. 2005; 31(3):173-85. DOI: 10.1016/j.ctrv.2005.03.008. View

Wagner L, Danks M . New therapeutic targets for the treatment of high-risk neuroblastoma. J Cell Biochem. 2009; 107(1):46-57. DOI: 10.1002/jcb.22094. View

Chang H, Chen T, Tai Y, Chen T, Chiu W, Chen R . Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab. 2010; 31(3):842-54. PMC: 3063630. DOI: 10.1038/jcbfm.2010.180. View

Abbott N, Ronnback L, Hansson E . Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2005; 7(1):41-53. DOI: 10.1038/nrn1824. View

Rao L, Perez D, White E . Lamin proteolysis facilitates nuclear events during apoptosis. J Cell Biol. 1996; 135(6 Pt 1):1441-55. PMC: 2133948. DOI: 10.1083/jcb.135.6.1441. View

Zhai H, Nakade K, Oda M, Mitsumoto Y, Akagi M, Sakurai J . Honokiol-induced neurite outgrowth promotion depends on activation of extracellular signal-regulated kinases (ERK1/2). Eur J Pharmacol. 2005; 516(2):112-7. DOI: 10.1016/j.ejphar.2005.04.035. View

Kotani H, Tanabe H, Mizukami H, Makishima M, Inoue M . Identification of a naturally occurring rexinoid, honokiol, that activates the retinoid X receptor. J Nat Prod. 2010; 73(8):1332-6. DOI: 10.1021/np100120c. View

Siddharthan V, Kim Y, Liu S, Kim K . Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells. Brain Res. 2007; 1147:39-50. PMC: 2691862. DOI: 10.1016/j.brainres.2007.02.029. View

10.

Garrido C, Galluzzi L, Brunet M, Puig P, Didelot C, Kroemer G . Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 2006; 13(9):1423-33. DOI: 10.1038/sj.cdd.4401950. View

11.

Lo Y, Teng C, Chen C, Chen C, Hong C . Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation. Biochem Pharmacol. 1994; 47(3):549-53. DOI: 10.1016/0006-2952(94)90187-2. View

12.

Esumi T, Makado G, Zhai H, Shimizu Y, Mitsumoto Y, Fukuyama Y . Efficient synthesis and structure-activity relationship of honokiol, a neurotrophic biphenyl-type neolignan. Bioorg Med Chem Lett. 2004; 14(10):2621-5. DOI: 10.1016/j.bmcl.2004.02.067. View

13.

Lin Y, Chang H, Chen T, Chang J, Chiu W, Lin J . Resveratrol protects against oxidized LDL-induced breakage of the blood-brain barrier by lessening disruption of tight junctions and apoptotic insults to mouse cerebrovascular endothelial cells. J Nutr. 2010; 140(12):2187-92. DOI: 10.3945/jn.110.123505. View

14.

Fried L, Arbiser J . Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal. 2009; 11(5):1139-48. PMC: 2842137. DOI: 10.1089/ars.2009.2440. View

15.

Chen R, Chen T, Chiu W, Chang C . Molecular mechanism of nitric oxide-induced osteoblast apoptosis. J Orthop Res. 2005; 23(2):462-8. DOI: 10.1016/j.orthres.2004.08.011. View

16.

Lin Y, Chen H, Ko C, Chan M . Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage. Eur J Pharmacol. 2006; 537(1-3):64-9. DOI: 10.1016/j.ejphar.2006.03.035. View

17.

Jiang Q, Fan L, Yang G, Guo W, Hou W, Chen L . Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model. BMC Cancer. 2008; 8:242. PMC: 2543046. DOI: 10.1186/1471-2407-8-242. View

18.

Hung T, Chen T, Liao M, Ho W, Liu D, Chuang W . Drynaria fortunei J. Sm. promotes osteoblast maturation by inducing differentiation-related gene expression and protecting against oxidative stress-induced apoptotic insults. J Ethnopharmacol. 2010; 131(1):70-7. DOI: 10.1016/j.jep.2010.05.063. View

19.

Cherng Y, Chang H, Lin Y, Kuo M, Chiu W, Chen R . Apoptotic insults to human chondrocytes induced by sodium nitroprusside are involved in sequential events, including cytoskeletal remodeling, phosphorylation of mitogen-activated protein kinase kinase kinase-1/c-Jun N-terminal kinase, and.... J Orthop Res. 2008; 26(7):1018-26. DOI: 10.1002/jor.20578. View

20.

Pearson A, Pinkerton C, Lewis I, Imeson J, Ellershaw C, Machin D . High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008; 9(3):247-56. DOI: 10.1016/S1470-2045(08)70069-X. View