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Open Access 01-12-2018 | Research

Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion

Authors: Haixia Wang, Youjun Luo, Tiankui Qiao, Zhaoxia Wu, Zhonghua Huang

Published in: Journal of Ovarian Research | Issue 1/2018

Abstract

Luteolin, a polyphenolic flavone, has been demonstrated to exert anti-tumor activity in various cancer types. Cisplatin drug resistance is a major obstacle in the management of ovarian cancer. In the present study, we investigated the chemo-sensitizing effect of luteolin in both cisplatin-resistant ovarian cancer cell line and a mice xenotransplant model. In vitro, CCK-8 assay showed that luteolin inhibited cell proliferation in a dose-dependent manner, and luteolin enhanced anti-proliferation effect of cisplatin on cisplatin-resistant ovarian cancer CAOV3/DDP cells. Flow cytometry revealed that luteolin enhanced cell apoptosis in combination with cisplatin. Western blotting and qRT-PCR assay revealed that luteolin increased cisplatin-induced downregulation of Bcl-2 expression. In addition, wound-healing assay and Matrigel invasion assay showed that luteolin and cisplatin synergistically inhibited migration and invasion of CAOV3/DDP cells. Moreover, in vivo, luteolin enhanced cisplatin-induced reduction of tumor growth as well as induction of apoptosis. We suggest that luteolin in combination with cisplatin could potentially be used as a new regimen for the treatment of ovarian cancer.

Rebecca L, Siegel M, Kimberly D, Miller M, Ahmedin Jemal DP. Cancer statistics, 2017. CA-CANCER J CLIN. 2017;67:7–30.CrossRef

van Driel WJ, Koole SN, Sikorska K, Schagen VLJ, Schreuder H, Hermans R, et al. Hyperthermic intraperitoneal chemotherapy in ovarian Cancer. N Engl J Med. 2018;378:230–40.CrossRef

Al RT, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, et al. Surgical cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev. 2013;2:D8765.

Dancey J. Targeted therapies and clinical trials in ovarian cancer. Ann Oncol. 2013;24:x59–63.CrossRef

Sundar S, Neal RD, Kehoe S. Diagnosis of ovarian cancer. BMJ. 2015;351:h4443.CrossRef

Gad Singer RSHK. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis. Am J Surg Pathol. 2005;29:218–24.CrossRef

Mantia-Smaldone GM, Edwards RP, Vlad AM. Targeted treatment of recurrent platinum-resistant ovarian cancer: current and emerging therapies. Cancer Manag Res. 2011;3:25–38.PubMed

Matsuura K, Huang N, Cocce K, Zhang L, Kornbluth S. Downregulation of the proapoptotic pr otein MOAP-1 by the UBR5 ubiquitin ligase and its role in ovarian cancer resistance to cisplatin. Oncogene. 2016;36:1698.CrossRef

Niero EL, Rocha-Sales B, Lauand C, Cortez BA, de Souza MM, Rezende-Teixeira P, et al. The multiple facets of drug resistance: one history, different approaches. J Exp Clin Cancer Res. 2014;33:37.CrossRef

10.

Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3:502–16.CrossRef

11.

Lopez-Lazaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem. 2009;9:31–59.CrossRef

12.

Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 2008;8:634–46.CrossRef

13.

Horinaka M, Yoshida T, Shiraishi T, Nakata S, Wakada M, Nakanishi R, et al. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene. 2005;24:7180–9.CrossRef

14.

Fang J, Zhou Q, Shi XL, Jiang BH. Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. Carcinogenesis. 2006;28:713–23.CrossRef

15.

Song S, Su Z, Xu H, Niu M, Chen X, Min H, et al. Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1. Cell Death Dis. 2017;8:e2612.CrossRef

16.

Ong C, Zhou J, Ong C, Shen H. Luteolin induces G1 arrest in human nasopharyngeal carcinoma cells via the Akt–GSK-3β–cyclin D1 pathway. Cancer Lett. 2010;298:167–75.CrossRef

17.

Chian SLYW. Luteolin sensitizes two Oxaliplatin-resistant colorectal Cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer Prev. 2014;15:2911–6.CrossRef

18.

Tu S, Ho C, Liu M, Huang C, Chang H, Chang C, et al. Luteolin sensitises drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem. 2013;141:1553–61.CrossRef

19.

Du H, Liu Y, Chen X, Yu X, Hou X, Li H, et al. DT-13 synergistically potentiates the sensitivity of gastric cancer cells to topotecan via cell cycle arrest in vitro and in vivo. Eur J Pharmacol. 2018;818:124–31.CrossRef

20.

Ren Y, Zhou X, Mei M, Yuan XB, Han L, Wang GX, et al. MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol. BMC Cancer. 2010;10:27.CrossRef

21.

ZJ J. About the evaluation of drug combination. Acta Pharmacol Sin. 2004;25:146–7.

22.

Baguley BC. Multiple drug resistance mechanisms in Cancer. Mol Biotechnol. 2010;46:308–16.CrossRef

23.

Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK, et al. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to Cancer therapeutics. Cancer Cell. 2017;31:142–56.CrossRef

24.

Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy MS, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104:19512–7.CrossRef

25.

Chen P, Hu T, Ma Y, Chen X, Dai L, Lei N, et al. Abstract 2808: Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450. Cancer Res. 2015;75:2808.CrossRef

26.

Xavier CPR, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M, Pereira-Wilson C. Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett. 2009;281:162–70.CrossRef

27.

Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. NAT REV MOL CELL BIO. 2014;15:49–63.CrossRef

28.

Inoue-Yamauchi A, Jeng PS, Kim K, Chen H, Han S, Ganesan YT, et al. Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy. Nat Commun. 2017;8:16078.CrossRef

29.

Cheng MCW EHYA. BCL-2, BCL-XL Emily H.-Y. A. Cheng,1 1 sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. MOL Cell. 2001;8:705–11.CrossRef

30.

PALMER JE, SANT CASSIA LJ, IRWIN CJ, MORRIS AG, ROLLASON TP. P53 and bcl-2 assessment in serous ovarian carcinoma. Int J Gynecol Cancer. 2008;18:241–8.CrossRef

31.

Fauvet R, Dufournet C, Poncelet C, Uzan C, Hugol D, Darai E. Expression of pro-apoptotic (p53, p21, bax, bak and fas) and anti-apoptotic (bcl-2 and bcl-x) proteins in serous versus mucinous borderline ovarian tumours. J Surg Oncol. 2005;92:337–43.CrossRef

32.

Wang H, Zhang Z, Wei X, Dai R. Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells. J OVARIAN RES. 2015;8:3.CrossRef

33.

Zheng CH, Zhang M, Chen H, Wang CQ, Zhang MM, Jiang JH, et al. Luteolin from Flos Chrysanthemi and its derivatives: new small molecule Bcl-2 protein inhibitors. Bioorg Med Chem Lett. 2014;24:4672–7.CrossRef

34.

Hudson LG, Zeineldin R, Stack MS. Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. CLIN EXP METASTAS. 2008;25:643–55.CrossRef

35.

Joseph E, BRKW DL. Progression and Enhancement of metastatic potential after exposure of tumor cells to chemotherapeutic Agents1. Cancer Res. 2001;61:2857–61.

36.

Yang JM, Xu Z, Wu H, Zhu H, Wu X, Hait WN. Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. Mol Cancer Res. 2003;1:420–7.PubMed

37.

Fu X, Tian J, Zhang L, Chen Y, Hao Q. Involvement of microRNA-93, a new regulator of PTEN/Akt signaling pathway, in regulation of chemotherapeutic drug cisplatin chemosensitivity in ovarian cancer cells. FEBS Lett. 2012;586:1279–86.CrossRef

38.

Matthew T, Cook YLCB. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells. Breast Cancer - Targets and Therapy. 2017;9:9–19.

39.

Ke-Hung Tsui LCTF. Upregulation of prostate-derived Ets factor by luteolin causes inhibition of cell proliferation and cell invasion in prostate carcinoma cells. Int J Cancer. 2011;130:2812–23.CrossRef

Title: Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion
Authors: Haixia Wang
Youjun Luo
Tiankui Qiao
Zhaoxia Wu
Zhonghua Huang
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2018
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/s13048-018-0468-y

At a glance: The ONWARDS insulin icodec trials

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Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion

Abstract

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Springer Medicine

Abstract

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