- Open Access
Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion
- Haixia Wang†1Email authorView ORCID ID profile,
- Youjun Luo†2,
- Tiankui Qiao2,
- Zhaoxia Wu3 and
- Zhonghua Huang1
© The Author(s). 2018
- Received: 12 April 2018
- Accepted: 4 November 2018
- Published: 19 November 2018
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.
- Cisplatin-resistant ovarian cancer
Ovarian cancer is one of the most common malignant tumors of gynecology, with the highest mortality compared with other gynecologic cancer because of its acute onset, rapid progress and high metastasis rate [1, 2]. Epithelial ovarian cancer (EOC) accounts for 85–90% of total ovarian carcinoma and is the most aggressive one. In early stage, surgical resection combined with chemotherapy is an effective therapy method . Unfortunately, most of the patients reach advanced stage at the time of diagnosis [4, 5]. For patients with advanced EOC, platinum-based chemotherapy is the standard of care. More than 80% of ovarian tumors response to first-line platinum-based therapy , however, the majority of patients acquire resistance to cisplatin (CDDP) treatment and ultimately result in relapse and poor prognosis [7, 8]. Therefore, it is necessary to develop appropriate combined reagents to solve drug resistance and enhance the sensitivity of EOC to cisplatin treatment.
Chemotherapy resistance is a key factor that limits the cure rate of ovarian cancer. The mechanisms underlying cancer cells resistance to cisplatin are not fully understood. It is acknowledged that various mechanisms are responsible for drug-resistance, including the decrease of the effective concentration of drugs in cells, the abnormalities of drug targets, and the abnormal regulation of cell apoptosis . Currently, there are some ways to overcome the chemo-resistance, such as maintenance therapy, novel cytotoxic agents, modulation of apoptosis and combination therapy . Natural medicine, with its small side effects and significant therapeutic effect, attracts a lot attention as a potential combination agent for cisplatin treatment.
Luteolin is one of the most common flavonoid compound that is widely existed in various plants including peppermint, rosemary, thyme, pinophyte, and pteridophyta . Numerous studies suggested that luteolin possesses a variety of pharmacological properties including anti-inflammatory, antiallergic, antioxidant, antimicrobial, immune regulation and anticancer activities [11, 12]. Among all these properties, anti-tumor effect has attracted a lot of attention. Researchers have found that luteolin exerts anti-tumor activities via several mechanisms, including cell cycle arrest, apoptosis induction, angiogenesis and metastasis inhibition [13–16]. A previous study has demonstrated that luteolin can sensitize oxaliplatin-resistant colorectal cancer cells to chemotherapeutic drugs through the inhibition of the Nrf2 pathway . Another study reported that luteolin can be used as a chemosensitizer to improve the therapeutic effect of tamoxifen in drug-resistant human breast cancer cells via the inhibition of cyclin E2 expression . These results suggest that luteolin exhibits potential chemosensitivity property for various cancers. However, whether luteolin can increase the chemotherapy sensitivity of cisplatin-resistant ovarian cancer and the underlying mechanisms is rarely reported, which needs to be further studied.
In the current study, we investigated the synergistic effects of luteolin combined with cisplatin in drug-resistant ovarian cancer cell line CAOV3/DDP both in vitro and in vivo, and tried to explore associated molecular mechanisms.
Reagents and cell lines
Luteolin was bought from Jin Sui Biological Technology (Shanghai, China). It was dissolved in DMSO as a stock of 500 mM and stored at − 20 °C. Cisplatin was purchased from QILU Pharmaceutical (Shandong, China). Human drug-resistant ovarian cancer cell line, CAOV3/DDP were obtained from the Shanghai Sixin Biotechnology company (Shanghai, China) and maintained in RPMI1640 (Gibco, Grand Island, NY, USA) containing 10% fetal bovine serum (Gibco, Grand Island, NY, USA). The cells were incubated at 37 °C in a humidified atmosphere with 5% CO2.
Cell proliferation assay
Cell proliferation was measured using Cell Counting Kit-8 (CCK-8; Dojindo Molecular Technologies, Inc., Kumamoto,Japan). Briefly, CAOV3/DDP cells (5 × 103) were seeded into 96-well plates and allowed for adhesion overnight. Then the cells were administrated with eight treatments as follows: control (culture medium); low-dose of luteolin (10 μM); medial-dose of luteolin (50 μM); high-dose of luteolin (100 μM); CDDP (2 μg/ml); CDDP (2 μg/ml) + low-dose of luteolin (10 μM); CDDP (2 μg/ml) + medial-dose of luteolin (50 μM); CDDP (2 μg/ml) + high-dose of luteolin (100 μM). After 48 h treatment, the culture medium was removed and CCK-8 was added according to the manufacturer’s instruction. Then the cells were incubated for 1–4 h at 37 °C and the absorbance was detected at 450 nm using a microplate reader. Cell proliferation was calculated as follows:
Cell proliferation (%) = [(OD of experiment group – OD of blank) / (OD of control group – OD of blank)] × 100%.
Cell apoptosis was detected using Annexin V-FITC Apoptosis Detection Kit (BD Pharmingen, Franklin Lakes, NJ, USA). Cells (2 × 104) were seeded into 6-well plates and treated with various concentration of luteolin (0, 10, 50, 100 μM) or CDDP alone or in combination for 48 h. Then both the adherent and floating cells were harvested and stained according to the manufacturer’s protocol. The apoptosis rate was analyzed by flow cytometry.
Cell migration ability was measured by wound-healing assay. Briefly, cells were seeded into 6-well plates and allowed to grow to a monolayer. Subsequently, a straight scratch was generated across the plate using a 200 μl pipet tip. The cells were washed with PBS and incubated with various concentration of luteolin (0, 10, 50, 100 μM) and CDDP alone or in combination (dissolve the chemicals in serum-free culture medium). Wound healing was observed and photographed at 0 and 48 h.
Matrigel invasion assay
The Matrigel was diluted in serum-free RPMI-1640 (RPMI-1640: Matrigel = 8:1) and added into the upper chamber. After treatment with various concentrations of luteolin (0, 10, 50, 100 μM) and CDDP alone or in combination for 48 h, the cells (5 × 104) were trypsinized and collected. 5 × 104 cells in 200 μl serum-free medium were seeded into the upper chamber. The lower chamber was filled with 600 μl complete medium containing 10% FBS. After incubation for 48 h, the invaded cells were stained with crystal violet and pictured under a microscope at x100 magnification.
Primer sequences for genes
CAOV3/DDP cells were seeded into 6-well plates (2 × 105/well),and treated with increasing doses of luteolin (0, 10, 50, 100 μM) or cisplatin (2 μg/ml) or both for 48 h. Then, the cells were harvested, and total proteins were extracted using cell lysis buffer (1 mM PMSF, 50 mM Tris (pH 8.1), 1% SDS, sodium pyrophosphate, β-glycerophosphate, sodium orthovanadate, sodium fluoride, EDTA, leupeptin and other inhibitors) (Beyotime Biotechnology, Shanghai, China. No. P0013G). The protein concentration was detected using BCA assay (Mai Bio Co., Ltd.). 20 μg proteins of each group were separated on SDS-PAGE, and then transferred onto PVDF membranes (Millipore Corp., Bedford, MA, USA). Membranes were blocked with 5% non-fat dry milk, and probed with primary antibodies against Bax (1:4000, Cell Signaling Technology, USA), Bcl-2 (1:4000, Cell Signaling Technology, USA), and β-Actin (1:5000, ProteinTech Group, Inc., USA) at 4 °C overnight. Then the membrane was washed with PBS and incubated with HRP-conjugated secondary antibodies (1:5000) for 1 h at room temperature. Finally, the blots were imaged with ECL (EMD Millipore).
In vivo xenograft experiment
Female BALB/c nude mice (5–6 weeks old) were obtained from the Shanghai Experimental Animal Center. Animals were raised in pathogen-free conditions at 22 °C, 50% humidity. Animal experiments were approved by the Institutional of Animal Care and Use Committee of Jinshan Hospital, Fudan University. The cisplatin resistant cell line CAOV3/DDP (5 × 106 cells) in a volume of 100 μl of PBS were inoculated in the subcutaneous tissue of the nude mice. Two weeks after implantation, the tumors were visible and the mice were randomly allocated into 8 groups (6 mice per group): (1) control group (normal saline); (2) luteolin low-dose (10 mg·kg− 1·d− 1) group; (3) luteolin medial-dose (20 mg·kg− 1·d− 1) group; (4) luteolin high-dose (40 mg·kg− 1·d− 1) group; (5) CDDP (3 mg·kg− 1·d− 1) group; (6) CDDP (3 mg·kg− 1·d− 1) plus luteolin low-dose (10 mg·kg− 1·d− 1) group; (7) CDDP (3 mg·kg− 1·d− 1) plus luteolin medial-dose (20 mg·kg− 1·d− 1) group; (8) CDDP (3 mg·kg− 1·d− 1) plus luteolin high-dose (40 mg·kg− 1·d− 1) group. The CDDP were intraperitoneal injected once daily, and luteolin were given by gavage once daily for 5 days. The tumor volume was measured three times a week. Three weeks after treatment, the mice were sacrificed, and the tumor volume and weight were measured. The tumor tissues were used for histopathologic examination.
Tumor paraffin tissue sections were processed with TUNEL assay to analyze apoptosis. The procedure was performed according to instructions of the TUNEL kit (KeyGen, Nanjing, China). The samples were observed under a microscope at × 100 magnification. The apoptotic cells were counted in three random fields for each sample, and the apoptosis percentage was calculated as follows: (Number of TUNEL-positive cells/Total number of cells in the field) × 100%.
Drug combination effect analysis
Combination effect between the luteolin and cisplatin was analyzed by the Zheng-Jun Jin method [19–21]. In this method, the combination rate was evaluated by the inhibition rate via the Q value. The formula for the Q value is: Q = Ea + b / (Ea + Eb - Ea × Eb), where Ea + b, Ea, and Eb are the inhibition rate of the combination group, drug a and drug b, respectively. Q = 1 would mean simple addition; Q > l, synergism or potentiation, Q < 1, antagonism.
All the experiments were repeated three times. The data were presented as mean ± SD. The difference between indicated groups were analyzed using Student’s t-test. P < 0.05 was considered be statistically significant.
Luteolin dose dependently enhanced the proliferation inhibition effect of cisplatin in CAOV3/DDP cells
Luteolin increased the sensitivity of CAOV3/DDP cells to cisplatin. The Q value was calculated to evaluate the effect of the combination of the two drugs. The inhibition rates were measured by CCK-8 assay. CDDP combined with luteolin (100 μM) showed a synergistic inhibitory effect on the proliferation of CAOV3/DDP cells (Q = 1.22 ± 0.04, > 1, P < 0.01). The data were expressed as the mean ± S.D. in triplicate
Inhibition rate (%)
Luteolin (100 μM)
69.1 ± 0.55
Luteolin (50 μM)
42.0 ± 1.20
Luteolin (10 μM)
−1.5 ± 6.26
CDDP (2 μg/ml)
30.2 ± 4.54
Luteolin (100 μM) + CDDP (2 μg/ml)
95.7 ± 0.24
1.22 ± 0.04
Luteolin (50 μM) + CDDP (2 μg/ml)
64.3 ± 1.22
1.08 ± 0.06
Luteolin (10 μM) + CDDP (2 μg/ml)
37.9 ± 3.02
1.36 ± 0.41
Luteolin enhanced cisplatin induced apoptosis in CAOV3/DDP cells
Luteolin and cisplatin decreased Bcl-2 expression synergistically
Luteolin combined with CDDP inhibited migration and invasion in CAOV3/DDP cells
Luteolin enhanced the anticancer effect of CDDP on ovarian cancer in vivo
Luteolin increased the sensitivity of xenograft model of ovarian cancer to cisplatin. The Q value was calculated to evaluate the effect of the combination of the two drugs. The inhibition rate in each group was measured by tumor weight reduction compared to the control group. CDDP combined with luteolin (40 mg) showed a synergistic inhibitory effect on the growth of xenograft tumor (Q = 1.16 ± 0.03, > 1, P < 0.01). The data were expressed as the mean ± S.D. in triplicate
Inhibition rate (%)
Luteolin (40 mg)
39 ± 1.64
Luteolin (20 mg)
34.4 ± 1.89
Luteolin (10 mg)
21.3 ± 6.83
CDDP (3 mg)
48.6 ± 1.55
Luteolin (40 mg) + CDDP (3 mg)
79.8 ± 3.5
1.16 ± 0.03
Luteolin (20 mg) + CDDP (3 mg)
62.8 ± 3.09
0.95 ± 0.03
Luteolin (10 mg) + CDDP (3 mg)
55.7 ± 1.64
0.94 ± 0.05
Combined treatment of CDDP with luteolin increases xenograft tumor cell apoptosis
Cisplatin is one of the most effective therapeutic agents widely used in clinic for the treatment of EOC. However, drug resistance is a major problem that limits its clinical application. Therefore, combination treatment with new sensitizing agents is an effective strategy to overcome cisplatin resistance . Luteolin, a flavonoid that has been identified in many plants, has demonstrated in numbers studies to exhibit chemopreventive or chemosensitising properties against various human cancers. In the current study, we provide experimental evidence both in vivo and in vitro that luteolin is able to enhance the therapeutic potential of cisplatin in ovarian cancer.
In the current study, firstly, we evaluated the effect of luteolin or cisplatin or the combination of both on the cell proliferation in human cisplatin-resistant ovarian cancer CAOV3/DDP cells. We found that luteolin alone inhibited the cell proliferation in a dose-dependent manner, and co-treatment with both agents could further decrease cell proliferation. These results suggested that luteolin could exert synergistic anti-proliferation effect with cisplatin in CAOV3/DDP cells.
Apoptosis inhibition is one of the main mechanisms responsible for the resistance of chemotherapy . Cisplatin is one of the most effective drugs for the treatment of ovarian cancer, and the mechanism involved in the process of its cytotoxicity include survival inhibition and apoptosis induction. Once the apoptotic pathway is blocked, tumor cells acquire resistance to pro-apoptotic effect of cisplatin, which reduces the antitumor effect of cisplatin . Therefore, inhibition of apoptosis is an effective strategy to overcome the drug resistance and promote the anti-tumor effect of cisplatin . Luteolin has been reported to induce apoptosis in various cancer cells such as human cervical cancer cells , esophageal carcinoma cells  and colorectal cancer cells . Our study found that the single treatment with luteolin could dose-dependently induce apoptosis in CAOV3/DDP cells, when combined with cisplatin, luteolin could significantly enhance cisplatin-induced cell apoptosis, indicating that luteolin enhanced the sensitivity of cisplatin, in part, through apoptosis induction.
The BCL-2 protein family plays a key role in the regulation of cell apoptosis. The BCL-2 protein family can be divided into three different subfamilies, including pro-survival factions such as BCL-2, MCL1 and BCL-XL, which inhibit the apoptosis process, and two pro-apoptotic subfamilies, the death effectors BAX and BAK and the BH3-only proteins such as BID, BIM and PUMA, which contribute to cell apoptosis [27–29]. Consequently, the ratio of Bcl-2/Bax is an essential factor to determine whether a tumor cell commits apoptosis or not. Overexpression of Bcl-2 can inhibit cell apoptosis, lead to resistance to cisplatin, and result in poor prognosis of cancer patients. Recent study has demonstrated that Bcl-2 is overexpressed in ovarian cancer [30, 31] and has a significant positive correlation with sensitivity to cisplatin in ovarian cancer cells . Therefore, targeting Bcl-2 may provide an effective therapeutic method to solve drug resistance in ovarian cancer. It was previously reported that luteolin could decrease Bcl-2 expression in various cancer cells . In the current study, results from qRT-PCR showed that luteolin at high concentration (100 μM) could significantly decrease the Bcl-2 mRNA level, and the combination of luteolin with cisplatin could evidently inhibit Bcl-2 expression compared with cisplatin alone. This suggests that the combined treatment induced cell apoptosis through the inhibition of Bcl-2 expression. The BCL-2 family proteins control the permeability of mitochondria and the release of cytochrome c to the cytoplasm, following the activation of a group of caspases, which proceeds apoptosis . This suggests that mitochondrial apoptosis pathway may be involved, and further study should be focused on the pathway.
Our data also revealed the potent antitumor effect of luteolin with cisplatin in ovarian cancer in vivo. Single treatment with increasing doses of luteolin showed growth inhibition in xenograft tumor. In addition, tumor volume and weight were significantly decreased in mice of combination treatment group compared with cisplatin alone. What’s more, the combination therapy synergistically induced more apoptosis than cisplatin, which is in consistent with in vitro study. These results further demonstrate that the inhibition of tumor growth was induced, in part, by the enhancement of cisplatin induced apoptosis.
Ovarian cancer is highly susceptible to occur metastasis in late stage. In most patients, though appearance of the lesion is still localized in the ovary, subclinical metastasis may already exist in many parts of the peritoneal or omentum . In addition, chemotherapy resistance leads to the decrease of chemotherapy sensitivity in ovarian cancer cells, and also enhance its malignant degree. It suggests that the occurrence of chemotherapy resistance is closely related to the promotion of invasion and metastasis in cancer cells [35, 36]. Cancer metastasis involves several processes including adhesion, migration, and invasion. Targeting these processes provides effective strategy to enhance the chemosensitivity of cisplatin . Luteolin has been proven to inhibit metastasis in various caner types such as breast cancer  and prostate cancer . In our experiment, wound-healing assay and Matrigel invasion assay showed that luteolin exhibited a dose-dependent suppression on migration as well as invasion in CAOV3/DDP cells. Additionally, the inhibition effect became stronger when treated the cells with both increasing concentrations of luteolin and cisplatin than single agent treatment. These results indicate that the improved anticancer effect of cisplatin in CAOV3/DDP cells by luteolin is partially mediated through inhibition in cell migration and invasion.
In conclusion, our study shows that luteolin, a natural flavonoid, significantly enhances the anti-tumor effect of cisplatin in ovarian cancer both in vivo and in vitro. Combination of luteolin and cisplatin is more effective in suppressing CAOV3/DDP cell growth and metastasis. Luteolin could enhance cisplatin induced apoptosis in cisplatin-resistant ovarian cancer CAOV3/DDP cells via decreasing Bcl-2 expression. Our preliminary data provide experimental evidence for potential clinical application of luteolin as a novel chemosensitizer in the chemotherapy in ovarian cancer.
We thank Longxiang Zhou, from Department of Science and Education, Jinshan branch of Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, and Guiping Gan, from Department of Obstetrics and Gynecology, Jinshan branch of Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, for their guidance and help in our work.
This study was supported by Science and Technology Innovation Fund Program of Jinshan District (2015-3-16).
Availability of data and materials
We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.
HW and YL both performed the study and wrote the manuscript, they contributed equally to this study. TQ reviewed and revised the article. ZW and ZH collected and analyzed the data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
There was no human participants, human data or human tissue involved in this manuscript.
Consent for publication
This manuscript has been read and approved by all the authors, the requirements for authors have been met and each author believes that the manuscript represents honest work.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Rebecca L, Siegel M, Kimberly D, Miller M, Ahmedin Jemal DP. Cancer statistics, 2017. CA-CANCER J CLIN. 2017;67:7–30.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.Google Scholar
- Dancey J. Targeted therapies and clinical trials in ovarian cancer. Ann Oncol. 2013;24:x59–63.View ArticleGoogle Scholar
- Sundar S, Neal RD, Kehoe S. Diagnosis of ovarian cancer. BMJ. 2015;351:h4443.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3:502–16.View ArticleGoogle Scholar
- Lopez-Lazaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem. 2009;9:31–59.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- ZJ J. About the evaluation of drug combination. Acta Pharmacol Sin. 2004;25:146–7.Google Scholar
- Baguley BC. Multiple drug resistance mechanisms in Cancer. Mol Biotechnol. 2010;46:308–16.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- Joseph E, BRKW DL. Progression and Enhancement of metastatic potential after exposure of tumor cells to chemotherapeutic Agents1. Cancer Res. 2001;61:2857–61.Google Scholar
- 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.PubMedGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.Google Scholar
- 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.View ArticleGoogle Scholar