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Published in: BMC Complementary Medicine and Therapies 1/2018

Open Access 01-12-2018 | Research article

Fisetin and polymeric micelles encapsulating fisetin exhibit potent cytotoxic effects towards ovarian cancer cells

Authors: Xue Xiao, Juan Zou, Yin Fang, Yibo Meng, Chao Xiao, Jiaxin Fu, Shiyu Liu, Peng Bai, Yuan Yao

Published in: BMC Complementary Medicine and Therapies | Issue 1/2018

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Abstract

Background

The anti-tumor activities of Natural compounds and their derivatives are of great interest to pharmaceutical industries. Fisetin is one of prospective natural compounds in this regard but unfortunately with poor hydrophilicity.

Methods

The effects of unmodified and modified fisetin in cultured ovarian cancer cells were compared by transmission electronmicroscopy to determine apoptotic bodies, MTT assay to quantitate cell numbers, and fluorescence activated cell sorting analyse of various markers to determine the apoptotic state. In addition, the efficacy of fisetin and fisetin-micelles in vivo was determined by using immunocompromised mice. Apoptosis was measured by established markers using both western blot analysis and immunochemistry. Angiogenesis in a xenograft mouse model carring SKOV3 cells was evaluated by color Doppler ultrasound and immunohistochemistry.

Result

Multiple lines of evidence indicated that fisetin and fisetin micelles induce apoptosis in ovarian cancer cells in a dose-dependent manner. Histological analysis, terminal deoxynucleotidyltransferase-mediated nick-end labeling assay, western blot, immunohistochemical detection and microvessel density detection demonstrated that fisetin and fisetin micelles induced increased tumor apoptosis, proliferation suppression and antiangiogenesis activities.

Conclusion

As far as we know, the present study is the first time to demonstrate the potency of both fisetin and fisetin micelles inducing apoptosis in ovarian cancer cells. Further studies will be needed to validate the therapeutic potential of fisetin and fisetin micelles in ovarian cancer treatment.
Literature
2.
go back to reference Li W, Cai JH, Zhang J, Tang YX, Wan L. Effects of cyclooxygenase inhibitors in combination with taxol on expression of cyclin D1 and Ki-67 in a xenograft model of ovarian carcinoma. Int J Mol Sci. 2012;13:9741–53.CrossRefPubMedPubMedCentral Li W, Cai JH, Zhang J, Tang YX, Wan L. Effects of cyclooxygenase inhibitors in combination with taxol on expression of cyclin D1 and Ki-67 in a xenograft model of ovarian carcinoma. Int J Mol Sci. 2012;13:9741–53.CrossRefPubMedPubMedCentral
3.
go back to reference Tripathi R, Samadder T, Gupta S, Surolia A, Shaha C. Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol Cancer Ther. 2011;10:255–68.CrossRefPubMed Tripathi R, Samadder T, Gupta S, Surolia A, Shaha C. Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol Cancer Ther. 2011;10:255–68.CrossRefPubMed
4.
go back to reference Suh Y, Afaq F, Johnson JJ, Mukhtar H. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 2009;30:300–7.CrossRefPubMed Suh Y, Afaq F, Johnson JJ, Mukhtar H. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 2009;30:300–7.CrossRefPubMed
5.
go back to reference Li Z, Guo X, Guan J. An oxygen release system to augment cardiac progenitor cell survival and differentiation under hypoxic condition. Biomaterials. 2012;33:5914–23.CrossRefPubMed Li Z, Guo X, Guan J. An oxygen release system to augment cardiac progenitor cell survival and differentiation under hypoxic condition. Biomaterials. 2012;33:5914–23.CrossRefPubMed
6.
go back to reference Chen WS, Lee YJ, Yu YC, Hsaio CH, Yen JH, Yu SH, Tsai YJ, Chiu SJ. Enhancement of p53-mutant human colorectal cancer cells radiosensitivity by flavonoid fisetin. Int J Radiat Oncol Biol Phys. 2010;77:1527–35.CrossRefPubMed Chen WS, Lee YJ, Yu YC, Hsaio CH, Yen JH, Yu SH, Tsai YJ, Chiu SJ. Enhancement of p53-mutant human colorectal cancer cells radiosensitivity by flavonoid fisetin. Int J Radiat Oncol Biol Phys. 2010;77:1527–35.CrossRefPubMed
7.
go back to reference Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT, Hsieh YH. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8−/caspase-3-dependent pathway. Arch Toxicol. 2012;86:263–73.CrossRefPubMed Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT, Hsieh YH. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8−/caspase-3-dependent pathway. Arch Toxicol. 2012;86:263–73.CrossRefPubMed
8.
go back to reference Hanneken A, Lin FF, Johnson J, Maher P. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci. 2006;47:3164–77.CrossRefPubMed Hanneken A, Lin FF, Johnson J, Maher P. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci. 2006;47:3164–77.CrossRefPubMed
9.
go back to reference Crozier A, Burns J, Aziz AA, Stewart AJ, Rabiasz HS, Jenkins GI, Edwards CA, Lean ME. Antioxidant flavonols from fruits, vegetables and beverages: measurements and bioavailability. Biol Res. 2000;33:79–88.CrossRefPubMed Crozier A, Burns J, Aziz AA, Stewart AJ, Rabiasz HS, Jenkins GI, Edwards CA, Lean ME. Antioxidant flavonols from fruits, vegetables and beverages: measurements and bioavailability. Biol Res. 2000;33:79–88.CrossRefPubMed
10.
go back to reference Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, Suemura M, Kawase I, Tanaka T. Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol. 2003;111:1299–306.CrossRefPubMed Higa S, Hirano T, Kotani M, Matsumoto M, Fujita A, Suemura M, Kawase I, Tanaka T. Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol. 2003;111:1299–306.CrossRefPubMed
11.
go back to reference Chen YC, Shen SC, Lee WR, Lin HY, Ko CH, Shih CM, Yang LL. Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch Toxicol. 2002;76:351–9.CrossRefPubMed Chen YC, Shen SC, Lee WR, Lin HY, Ko CH, Shih CM, Yang LL. Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch Toxicol. 2002;76:351–9.CrossRefPubMed
12.
go back to reference Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 2006;9:68–76.CrossRefPubMed Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 2006;9:68–76.CrossRefPubMed
13.
go back to reference Haddad AQ, Fleshner N, Nelson C, Saour B, Musquera M, Venkateswaran V, Klotz L. Antiproliferative mechanisms of the flavonoids 2,2′-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr Cancer. 2010;62:668–81.CrossRefPubMed Haddad AQ, Fleshner N, Nelson C, Saour B, Musquera M, Venkateswaran V, Klotz L. Antiproliferative mechanisms of the flavonoids 2,2′-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr Cancer. 2010;62:668–81.CrossRefPubMed
14.
go back to reference Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010;333:169–80.CrossRefPubMed Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010;333:169–80.CrossRefPubMed
15.
go back to reference Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis. 2010;31:1424–33.CrossRefPubMedPubMedCentral Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis. 2010;31:1424–33.CrossRefPubMedPubMedCentral
16.
go back to reference Touil YS, Auzeil N, Boulinguez F, Saighi H, Regazzetti A, Scherman D, Chabot GG. Fisetin disposition and metabolism in mice: identification of geraldol as an active metabolite. Biochem Pharmacol. 2011;82:1731–9.CrossRefPubMed Touil YS, Auzeil N, Boulinguez F, Saighi H, Regazzetti A, Scherman D, Chabot GG. Fisetin disposition and metabolism in mice: identification of geraldol as an active metabolite. Biochem Pharmacol. 2011;82:1731–9.CrossRefPubMed
17.
go back to reference Ansó E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, Martínez-Irujo JJ. Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. Biochem Pharmacol. 2010;79:1600–9.CrossRefPubMed Ansó E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, Martínez-Irujo JJ. Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. Biochem Pharmacol. 2010;79:1600–9.CrossRefPubMed
18.
go back to reference Wu MY, Hung SK, Fu SL. Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-κB activity. J Agric Food Chem. 2011;59:10496–504.CrossRefPubMed Wu MY, Hung SK, Fu SL. Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-κB activity. J Agric Food Chem. 2011;59:10496–504.CrossRefPubMed
19.
go back to reference Kim JY, Jeon YK, Jeon W, Nam MJ. Fisetin induces apoptosis in Huh-7 cells via downregulation of BIRC8 and Bcl2L2. Food Chem Toxicol. 2010;48:2259–64.CrossRefPubMed Kim JY, Jeon YK, Jeon W, Nam MJ. Fisetin induces apoptosis in Huh-7 cells via downregulation of BIRC8 and Bcl2L2. Food Chem Toxicol. 2010;48:2259–64.CrossRefPubMed
20.
go back to reference Chen Y, Wu Q, Song L, He T, Li Y, Li L, Su W, Liu L, Qian Z, Gong C. Polymeric micelles encapsulating fisetin improve the therapeutic effect in colon cancer. ACS Appl Mater Interfaces. 2015;7:534–42.CrossRefPubMed Chen Y, Wu Q, Song L, He T, Li Y, Li L, Su W, Liu L, Qian Z, Gong C. Polymeric micelles encapsulating fisetin improve the therapeutic effect in colon cancer. ACS Appl Mater Interfaces. 2015;7:534–42.CrossRefPubMed
22.
go back to reference Hopkins TG, Mura M, Al-Ashtal HA, Lahr RM, Abd-Latip N, Sweeney K, Lu H, Weir J, El-Bahrawy M, Steel JH, Ghaem-Maghami S, Aboagye EO. The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer. Nucleic Acids Res. 2016 Feb;18:1227–46.CrossRef Hopkins TG, Mura M, Al-Ashtal HA, Lahr RM, Abd-Latip N, Sweeney K, Lu H, Weir J, El-Bahrawy M, Steel JH, Ghaem-Maghami S, Aboagye EO. The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer. Nucleic Acids Res. 2016 Feb;18:1227–46.CrossRef
23.
go back to reference Echarri GMJ, Green R, Muggia FM. Intraperitoneal drug delivery for ovarian cancer: why, how, who, what, and when. Oncology (Williston Park). 2011;25:156–65. 170 Echarri GMJ, Green R, Muggia FM. Intraperitoneal drug delivery for ovarian cancer: why, how, who, what, and when. Oncology (Williston Park). 2011;25:156–65. 170
24.
go back to reference Li QQ, Lee RX, Liang H, Zhong Y, Reed E. Enhancement of cisplatin-induced apoptosis by β-elemene in resistant human ovarian cancer cells. Med Oncol. 2013;30:424.CrossRefPubMedPubMedCentral Li QQ, Lee RX, Liang H, Zhong Y, Reed E. Enhancement of cisplatin-induced apoptosis by β-elemene in resistant human ovarian cancer cells. Med Oncol. 2013;30:424.CrossRefPubMedPubMedCentral
25.
go back to reference McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1–6.CrossRefPubMed McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1–6.CrossRefPubMed
26.
go back to reference Khan N, Asim M, Afaq F, Abu ZM, Mukhtar H. A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice. Cancer Res. 2008;68:8555–63.CrossRefPubMedPubMedCentral Khan N, Asim M, Afaq F, Abu ZM, Mukhtar H. A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice. Cancer Res. 2008;68:8555–63.CrossRefPubMedPubMedCentral
27.
go back to reference Kozics K, Valovicova Z, Slamenova D. Structure of flavonoids influences the degree inhibition of benzo(a)pyrene - induced DNA damage and micronuclei in HepG2 cells. Neoplasma. 2011;58:516–24.CrossRefPubMed Kozics K, Valovicova Z, Slamenova D. Structure of flavonoids influences the degree inhibition of benzo(a)pyrene - induced DNA damage and micronuclei in HepG2 cells. Neoplasma. 2011;58:516–24.CrossRefPubMed
28.
go back to reference Katalinić M, Rusak G, Domaćinović BJ, Sinko G, Jelić D, Antolović R, Kovarik Z. Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase. Eur J Med Chem. 2010;45:186–92.CrossRefPubMed Katalinić M, Rusak G, Domaćinović BJ, Sinko G, Jelić D, Antolović R, Kovarik Z. Structural aspects of flavonoids as inhibitors of human butyrylcholinesterase. Eur J Med Chem. 2010;45:186–92.CrossRefPubMed
29.
go back to reference López-Lázaro M, Willmore E, Austin CA. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res. 2010;696:41–7.CrossRefPubMed López-Lázaro M, Willmore E, Austin CA. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res. 2010;696:41–7.CrossRefPubMed
30.
go back to reference Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H, Tian B. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 2011;108:84–93.CrossRefPubMed Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H, Tian B. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 2011;108:84–93.CrossRefPubMed
31.
go back to reference Khan N, Afaq F, Khusro FH, Mustafa AV, Suh Y, Mukhtar H. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer. 2012;130:1695–705.CrossRefPubMed Khan N, Afaq F, Khusro FH, Mustafa AV, Suh Y, Mukhtar H. Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer. 2012;130:1695–705.CrossRefPubMed
Metadata
Title
Fisetin and polymeric micelles encapsulating fisetin exhibit potent cytotoxic effects towards ovarian cancer cells
Authors
Xue Xiao
Juan Zou
Yin Fang
Yibo Meng
Chao Xiao
Jiaxin Fu
Shiyu Liu
Peng Bai
Yuan Yao
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2018
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-018-2127-7

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