Honokiol induces apoptotic cell death by oxidative burst and mitochondrial hyperpolarization of bladder cancer cells

Hsiao,Chi‑Hao; Yao,Chih‑Jung; Lai,Gi‑Ming; Lee,Liang‑Ming; Whang‑Peng,Jacqueline; Shih,Ping‑Hsiao

doi:10.3892/etm.2019.7419

Honokiol induces apoptotic cell death by oxidative burst and mitochondrial hyperpolarization of bladder cancer cells

Authors:
- Chi‑Hao Hsiao
- Chih‑Jung Yao
- Gi‑Ming Lai
- Liang‑Ming Lee
- Jacqueline Whang‑Peng
- Ping‑Hsiao Shih
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Affiliations: Department of Urology, Wan Fang Hospital, Taipei 11696, Taiwan R.O.C., Cancer Center, Wan Fang Hospital, Taipei 11696, Taiwan R.O.C., Center for Cell Therapy, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan R.O.C.
Published online on: March 20, 2019 https://doi.org/10.3892/etm.2019.7419
Pages: 4213-4222

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Abstract

Bladder cancer is one of the most common types of malignant tumor worldwide. Current treatments, including chemo‑/radiotherapy, only have limited efficacy on bladder cancer progression. Honokiol is an active component of Magnolia officinalis with multiple biological effects that may provide promising health benefits. In the present study, the anti‑cancer properties of honokiol against bladder cancer cells were investigated by flow cytometric analysis. The results revealed that honokiol exhibited significant anti‑proliferative effects on bladder cancer cell lines, particularly on BFTC‑905 human transitional cell carcinoma cells. Furthermore, honokiol at low doses (≤25 µM) induced cell cycle arrest in G0/G1 phase, while it induced significant apoptotic cell death at high doses (≥50 µM; P<0.05). Furthermore, a significant accumulation of reactive oxygen species was identified in honokiol‑treated cells. In addition, honokiol induced hyperpolarization of the mitochondrial membrane, which may lead to mitochondrial dysfunction. Finally, caspase‑3/7 activation was identified in high‑dose honokiol‑treated bladder cancer cells. These results suggest that honokiol induces apoptosis via the mitochondrial pathway and honokiol‑containing traditional herbal remedies may have a potential clinical application in the treatment of bladder cancer.

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1	American Cancer Society. Cancer Facts & Figures. 2018.
2	Cancer Prevention Group: Annual Report of Taiwan Cancer Registry for 2016. December 27–2018, https://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=269&pid=10227
3	Huang CY, Lin YC, Shiue HS, Chen WJ, Su CT, Pu YS, Ao PL and Hsueh YM: Comparison of arsenic methylation capacity and polymorphisms of arsenic methylation genes between bladder cancer and upper tract urothelial carcinoma. Toxicol Lett. 295:64–73. 2018. View Article : Google Scholar : PubMed/NCBI
4	Boulanger M, Tual S, Lemarchand C, Guizard AV, Velten M, Marcotullio E, Baldi I, Clin B and Lebailly PP: Agricultural exposure and risk of bladder cancer in the AGRIculture and CANcer cohort. Int Arch Occup Environ Health. 90:169–178. 2017. View Article : Google Scholar : PubMed/NCBI
5	Mendez WM Jr, Eftim S, Cohen J, Warren I, Cowden J, Lee JS and Sams R: Relationships between arsenic concentrations in drinking water and lung and bladder cancer incidence in U.S. counties. J Expo Sci Environ Epidemiol. 27:235–243. 2017. View Article : Google Scholar : PubMed/NCBI
6	Shibata A, Ohneseit PF, Tsai YC, Spruck CH III, Nichols PW, Chiang HS, Lai MK and Jones PA: Mutational spectrum in the p53 gene in bladder tumors from the endemic area of black foot disease in Taiwan. Carcinogenesis. 15:1085–1087. 1994. View Article : Google Scholar : PubMed/NCBI
7	NNational Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN GuidelinesÒ). Bladder cancer Version 2.2018. February 7–2018.https://oncolife.com.ua/doc/nccn/Bladder_Cancer.pdf
8	Shelley MD, Mason MD and Kynaston H: Intravesical therapy for superficial bladder cancer: A systematic review of randomised trials and meta-analyses. Cancer Treat Rev. 36:195–205. 2010. View Article : Google Scholar : PubMed/NCBI
9	Koga F, Takemura K and Fukushima H: Biomarkers for predicting clinical outcomes of chemoradiation-based bladder preservation therapy for muscle-invasive bladder cancer. Int J Mol Sci. 19:E27772018. View Article : Google Scholar : PubMed/NCBI
10	Rauf A, Patel S, Imran M, Maalik A, Arshad MU, Saeed F, Mabkhot YN, Al-Showiman SS, Ahmad N and Elsharkawy E: Honokiol: An anticancer lignan. Biomed Pharmacother. 107:555–562. 2018. View Article : Google Scholar : PubMed/NCBI
11	Zubair H, Azim S, Ahmad A, Khan MA, Patel GK, Singh S and Singh AP: Cancer chemoprevention by phytochemicals: Nature's healing touch. Molecules. 22:E3952017. View Article : Google Scholar : PubMed/NCBI
12	Lee YJ, Lee YM, Lee CK, Jung JK, Han SB and Hong JT: Therapeutic applications of compounds in the magnolia family. Pharmacol Ther. 130:157–176. 2011. View Article : Google Scholar : PubMed/NCBI
13	Kumar A, Kumar Singh U and Chaudhary A: Honokiol analogs: A novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med Chem. 5:809–829. 2013. View Article : Google Scholar : PubMed/NCBI
14	Prasad R and Katiyar SK: Honokiol, an active compound of Magnolia plant, inhibits growth, and progression of cancers of different organs. Adv Exp Med Biol. 928:245–265. 2016. View Article : Google Scholar : PubMed/NCBI
15	Chio CC, Chen KY, Chang CK, Chuang JY, Liu CC, Liu SH and Chen RM: Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells. BMC Cancer. 18:3792018. View Article : Google Scholar : PubMed/NCBI
16	Chio CC, Tai YT, Mohanraj M, Liu SH, Yang ST and Chen RM: Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway. Phytomedicine. 49:41–51. 2018. View Article : Google Scholar : PubMed/NCBI
17	Lai IC, Shih PH, Yao CJ, Yeh CT, Whang-Peng J, Lui TN, Chuang SE, Hu TS, Lai TY and Lai GM: Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells. PLoS One. 10:e01148302015. View Article : Google Scholar : PubMed/NCBI
18	Chang MT, Lee SP, Fang CY, Hsieh PL, Liao YW, Lu MY, Tsai LL, Yu CC and Liu CM: Chemosensitizing effect of honokiol in oral carcinoma stem cells via regulation of IL-6/Stat3 signaling. Environ Toxicol. 33:1105–1112. 2018. View Article : Google Scholar : PubMed/NCBI
19	Zhang Q, Zhao W, Ye C, Zhuang J, Chang C, Li Y, Huang X, Shen L, Li Y, Cui Y, et al: Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis. Oncotarget. 6:37335–37348. 2015. View Article : Google Scholar : PubMed/NCBI
20	Shen L, Zhang F, Huang R, Yan J and Shen B: Honokiol inhibits bladder cancer cell invasion through repressing SRC-3 expression and epithelial-mesenchymal transition. Oncol Lett. 14:4294–4300. 2017. View Article : Google Scholar : PubMed/NCBI
21	Vichai V and Kirtikara K: Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 1:1112–1116. 2006. View Article : Google Scholar : PubMed/NCBI
22	Monappa V, Reddy SM and Kudva R: Hematolymphoid neoplasms in effusion cytology. Cytojournal. 15:152018. View Article : Google Scholar : PubMed/NCBI
23	Danova M, Torchio M, Comolli G, Sbrana A, Antonuzzo A and Mazzini G: The role of automated cytometry in the new era of cancer immunotherapy. Mol Clin Oncol. 9:355–361. 2018.PubMed/NCBI
24	Li CG, Ni CL, Yang M, Tang YZ, Li Z, Zhu YJ, Jiang ZH, Sun B and Li CJ: Honokiol protects pancreatic beta cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo. Biomed Pharmacother. 97:1229–1237. 2018. View Article : Google Scholar : PubMed/NCBI
25	Wang H, Liao Z, Sun X, Shi Q, Huo G, Xie Y, Tang X, Zhi X and Tang Z: Intravenous administration of Honokiol provides neuroprotection and improves functional recovery after traumatic brain injury through cell cycle inhibition. Neuropharmacology. 86:9–21. 2014. View Article : Google Scholar : PubMed/NCBI
26	Liu JX, Shen SN, Tong Q, Wang YT and Lin LG: Honokiol protects hepatocytes from oxidative injury through mitochondrial deacetylase SIRT3. Eur J Pharmacol. 834:176–187. 2018. View Article : Google Scholar : PubMed/NCBI
27	Halasi M, Hitchinson B, Shah BN, Váraljai R, Khan I, Benevolenskaya EV, Gaponenko V, Arbiser JL and Gartel AL: Honokiol is a FOXM1 antagonist. Cell Death Dis. 9:842018. View Article : Google Scholar : PubMed/NCBI
28	Kroemer G, Galluzzi L and Brenner C: Mitochondrial membrane permeabilization in cell death. Physiol Rev. 87:99–163. 2007. View Article : Google Scholar : PubMed/NCBI
29	Green DR and Llambi F: Cell death signaling. Cold Spring Harb Perspect Biol. 7:a0060802015. View Article : Google Scholar : PubMed/NCBI
30	Hua H, Chen W, Shen L, Sheng Q and Teng L: Honokiol augments the anti-cancer effects of oxaliplatin in colon cancer cells. Acta Biochim Biophys Sin (Shanghai). 45:773–779. 2013. View Article : Google Scholar : PubMed/NCBI