v
Search
Advanced Search

Publications > Journals > Journal of Exploratory Research in Pharmacology > Article Full Text

  • Review Article
  • OPEN ACCESS

Luteolin: Anti-breast Cancer Effects and Mechanisms

  • Ying Wang,
  • Jing Wang,
  • Xing Gong,
  • Xinxuan Wen and
  • Xinsheng Gu*
 Author information  Cite
Journal of Exploratory Research in Pharmacology   2018;3(3):85-90

doi: 10.14218/JERP.2018.00011

Abstract

Luteolin is a flavonoid compound and exhibits antioxidant, antiinflammatory, antibacterial, antidiabetic and antiproliferative properties. Studies have shown that luteolin may inhibit cell proliferation, metastasis, and angiogenesis of numerous types of cancers, including breast cancer, through inducing cell cycle arrest and apoptosis and by modulating cell signaling. In this review, we have summarized the recent studies on inhibitory effects and underlying mechanisms of luteolin in breast cancer. These studies support that luteolin is a promising drug to treat breast cancer.

Keywords

Luteolin, Breast Cancer, Mechanisms, Inhibitory Effects

Introduction

Luteolin is the nickname of 3′, 4′, 5, 7-tetrahydroxyflavone. It belongs to biologically active flavonoids that are widely found in the plant kingdom.1 Dietary intake of flavonoids is inversely associated with risk of lung, prostate, stomach and breast cancers in humans.2–4 Luteolin contains three rings in its molecule, including two benzene rings (A, B) and an oxygen-containing (C) ring, which is called the C6-C3-C6 structure (Fig. 1). There is a C2-3 double bond in the oxygen-containing (C) ring, and two hydroxyl groups in each benzene ring.5 Luteolin does not have an –OH substitution on C3.6 The C2-3 double bond and C3′ and C4′ hydroxyl groups of luteolin are essential for its biochemical and biological activities,7 including antioxidant, antiinflammatory, antibacterial, antidiabetic and antiproliferative actions.8,9 In the past decades, the anticancer effect of luteolin has been demonstrated on many kinds of cancers, such as hepatocellular carcinoma, melanoma, and gastric carcinoma, ovarian cancer, colorectal cancer, and breast cancers.10–22

Luteolin molecular structure.
Fig. 1  Luteolin molecular structure.

The C2-3 double bond and C3′ and C4′ hydroxyl groups of luteolin are essential for the biochemical and biological activities.

Breast cancer is the most common and life-threatening cancer diagnosed among women worldwide.23 According to genomic expression profiles and immunohistochemical staining of a few molecular markers, such as estrogen receptor (ER), PR, Her2, and Ki67, breast cancer is classified into the following five subtypes: luminal A (ER/PR+HER2−Ki-67low), luminal B (ER/PR+HER2−/+Ki-67high), Her-2-enriched (ER/PR−HER2+Ki-67high), triple negative/basal-like (ER/PR−HER2−Ki-67high), and “other” (including all those that cannot be attributed to the four subtypes). This molecular classification predicts cancer progression and directs the choice of therapeutic modality.24–29

Patients with high expression of HER-2 and Ki-67 were found to have a poor prognosis.30,31 The luminal A subtype is more responsive to endocrine therapy than other subtypes. The luminal B subtype can be treated by chemotherapy. The Her-2-enriched subtype is treated by HER-2-targeted therapy, and anthracycline-based chemotherapy. The triple negative/basal-like subtype is treated by platinum-based chemotherapy and PARP inhibitors.24–29

Although therapeutic approaches for breast cancer have been developed, the cure of breast cancer is still unsatisfactory because of the heterogeneity and recalcitrant nature towards various drug therapies.24–29,32 To control proliferation and metastasis during breast cancer therapy, novel drugs are needed. In this paper, we have summarized the studies on the anticancer effects of luteolin on breast cancer.

Anticancer effects of luteolin on breast cancer

The anticancer effects of luteolin on breast cancer have been investigated using pertinent cell lines which are relevant to molecular subtypes of breast cancer.33 Luteolin was shown to effectively block the IGF-1-stimulated luminal A subtype ERα-positive MCF-7 cell proliferation in a dose- and time-dependent manner34 and to suppress triple negative/basal-like ERα-negative MDA-MB-231 cell growth.35 Luteolin was also shown to decrease the viability of breast cancer cells MCF7/6 and MDA-MB231-1833.36 Luteolin-supplementation at 0.01% or 0.05% significantly reduced tumor burden in nude mice inoculated with MDA-MB-231 cells.35 This was confirmed by studies that showed dose-dependent inhibitory effects of luteolin on the proliferation of MCF-7 cells and MDA-MB-231 cells.37,38

Extensive studies have shown that luteolin significantly inhibits cell cycle of MCF-7 and MDA-MB-231 cells, resulting in cell cycle arrest at the G2/M and S stages.34,38–40 Luteolin can also induce apoptosis in breast cancer cells.34–36 These studies support that luteolin inhibits the proliferation of breast cancer cells of various subtypes. In an epidemiological study on dietary intake of selected flavonols, flavones and flavonoids, luteolin in food was shown to have no anticancer effect.41 This might be due to low daily uptake of luteolin (<2.0 mg/d). The therapeutic doses or concentration of luteolin are much higher and could be 10–30 mg/mL according to the experimental research findings.

The formation of new blood vessels from the preexisting vasculature (angiogenesis) is a crucial stage in cancer progression. Indeed, studies showed that luteolin exerted strong antiangiogenesis activity in chick chorioallantoic membrane.38,42 Metastases are the primary cause of human cancer deaths. Most breast cancer-related deaths from triple negative breast cancer (TNBC) occur following metastasis of cancer cells and development of tumors at secondary sites. Because TNBCs lack the three receptors (ER, PR, and HER2) targeted by current chemotherapeutic regimens, they are typically treated with extremely aggressive and highly toxic nontargeted treatment strategies.

Luteolin can efficiently suppress migration and invasion of the highly metastatic TNBC cell lines MDA-MB-231 and BT-549, and inhibit the lung metastases of breast cancer xenograft tumors derived from MDA-MD-231 cells.38,42–44 Luteolin can also significantly inhibit migration of ERα-positive MCF-7,38 inhibit cell migration and viability of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells in vitro, and suppress metastasis of these cells to the lungs in a mouse metastasis model.44 Luteolin may inhibit breast cancer intravasation through the lymphatic barrier, as revealed by an in vitro assay that showed luteolin exerted an antiintravasative effect of MDA-MB231 breast cancer spheroids through the lymph endothelial barrier.45 Luteolin can efficiently suppress the migration and invasion of MDA-MB-231 and MCF-7 cells as well.38,42–45 Epithelial mesenchymal transition (EMT) is also a key event in metastasis. Luteolin can reverse EMT of MDA-MB-231 and BT5-49 breast cancer cells, which may be mediated by down-regulation of β-catenin.43

All these studies support that luteolin may induce cell cycle arrest at the G2/M and S stages, as well as apoptosis, and inhibit migration and epithelial mesenchymal trans-differentiation of breast cancer cells, thereby inhibiting the development, progression and metastasis of breast cancer.

Mechanism involved in anticancer effects of luteolin on breast cancer

Apoptotic pathways

Luteolin-induced apoptosis involves reactive oxygen species (ROS) generation, DNA damage, activation of the ATR→Chk2→p53 signaling pathway, inhibition of the nuclear factor (NF)-κB signaling pathway, activation of the p38 pathway and depletion of antiapoptotic proteins.46 In MCF-7 cells, luteolin enhanced the expression of death receptors, such as DR5, and enhanced the activities of caspase-8 and -9, which in turn induced caspase-3 activity in a dose-dependent manner, followed by inactivation of PARP. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and increased Bax expression by inhibiting expression of Bcl-2. Therefore, luteolin induces apoptosis by activating the extrinsic and intrinsic pathways.47

PI3K/Akt

Luteolin markedly decreases IGF-1-dependent IGF-1R and Akt phosphorylation without affecting extracellular signal-regulated kinase (ERK)1/2 phosphorylation in MCF-7 cells, and the inhibiting IGF-1-mediated PI3K-Akt pathway is dependent on ERα expression, resulting in suppression of MCF-7 cells.34 Luteolin induces cell cycle arrest and apoptosis in breast cancer cells through inhibition of PI3K/Akt activation and increase of FOXO3a activation.40 Inhibiting the PI3K/Akt signaling pathways also mediated suppression of the epidermal growth factor receptor (EGFR) signaling pathway and the proliferation of ERα-positive MCF-7 cells and ERα-negative MDA-MB-231 cells by luteolin in a dose-dependent manner.37

EGFR

EGFRs/HERs are implicated in pathogenesis of breast cancer and their over-expression is associated with poorer prognosis and outcomes of breast cancer.48–50 Luteolin was shown to down-regulate EGFR expression and inhibit EGF-induced mitogen-activated protein kinase (MAPK) activation in a dose-dependent manner, including the phosphorylation of ERK, p38 and AKT, and to suppress the proliferation of MDA-MB-231 ER-negative breast cancer cells and ERα-positive MCF-7 cells.35,37

Polo-like kinase 1 (PLK-1)

PLK-1 is a mitotic kinase and actively regulates the G2/M transition, mitosis, mitotic exit, and cytokinesis.51 The over-expression of PLK-1 is strongly correlated with a wide spectrum of human cancers and their poor prognosis.52 Luteolin inhibits PLK1 gene expression in MCF-7 breast cancer cells53 and MDA-MB-231 ER-negative breast cancer cells.35 This inhibition is probably caused by decreased acetylation of histone H4 associated with the PLK1 gene promoter.53

Estrogen signaling

It has been shown that luteolin possesses estrogen agonist activity.54 However, luteolin exerts its antiestrogen activity by regulating many estrogen signaling pathway (ESP) genes, including GTF2H2, NCOR1, TAF9, NRAS, NRIP1, POLR2A, DDX5 and NCOA3, in MCF-7 breast cancer cells probably through epigenetic mechanism.53 Some breast cancer subtypes, such as luminal A, are considered to be primarily regulated by ESPs, and hormone therapy using antiestrogen drugs, such as tamoxifen, is effective for breast cancers expressing ERα.55–57 Therefore, luteolin could be an effective drug for breast cancer therapy.

Notch and microRNA

Luteolin inhibits Notch signaling and regulates miRNAs. Treatment of MCF-7 and MDA-MB-231 cells with luteolin results in decreasing expression levels of Notch-1, Hes-1, Hey-1, Hey-2 as well as vascular endothelial growth factor (VEGF), cyclin D1 and matrix metalloproteinase (MMP) expression in breast cancer cells. Luteolin induces miR-181a, miR-139-5p, miR-224 and miR-246 expression levels and decreases the miR-155 level in both MCF-7 and MDA-MB-231 cells, and increases miR-34a level in MDA-MB-231 cells. MiR-34a and miR-224 regulates Notch signaling and inhibits breast cancer cell survival migration and angiogenesis.38

Inflammation-related signaling

Luteolin down-regulates the transactivity of NF-κB and activator protein-1 (AP-1), resulting in inhibition of TNFα-induced COX-2 expression. Luteolin also inhibits TNFα-induced phosphorylation of MAPK/ERK kinase 1/ERK/p90RSK, MAPK kinase 4/Jun N-terminal kinase (c-JNK)/c-Jun, and Akt/p70S6K. These effects of luteolin are probably due to blocking tumor progression via locus 2 serine/threonine kinase (TPL2).58

Metastasis-associated signaling

Luteolin down-regulates the expression of astrocyte elevated gene 1 (AEG-1), a novel oncoprotein, and MMP-2.42 Relatively low levels of luteolin significantly inhibit VEGF secretion in MDA-MB-231 (4175) LM2 cells, suggesting that it has the ability to suppress a potent angiogenic and cell survival factor.44 Luteolin suppresses the metastasis of TNBC by reversing EMT via down-regulation of beta-catenin expression.43

Luteolin directly inhibits kinases protein kinase C (PKC), VRK1 and TLP2 in breast cancer cells

As reported as early as 1989, luteolin is a PKC inhibitor. It competitively blocks the ATP binding site on the catalytic unit of PKC.59 TPL2 is a protooncogene that is over-expressed in various cancer types, including breast cancer.60 Luteolin may directly bind TPL2 and inhibit TPL2 activity in an ATP-competitive manner,58 leading to similar effects of luteolin on TNF-α-mediated signaling pathways and COX-2 expression.58 Recently, luteolin was found to significantly and directly interact with the catalytic domain of vaccinia-related kinase 1 (VRK1), a mitotic kinase that functions in cell cycle regulation, and to reduce VRK1-mediated phosphorylation of the cell cycle-related substrates BAF and histone H3.61 Therefore, luteolin is a direct inhibitor for kinases such as PKC, VRK1, and TLP2.

Luteolin inhibits fatty acid synthase in breast cancer cells

Luteolin inhibits fatty acid synthase (FAS), which is a key lipogenic enzyme over-expressed in many human cancers, resulting in inhibition of cell growth and induction of apoptosis of prostate and breast cancer cells.39,62 Although the underlying mechanism of FAS inhibition by luteolin is not completely clear, the presence of a C-2,3 double bond, a 4-ketone function and hydroxyl groups on positions 5, 7, 3′, and 4′ plays a favorable role to inhibit lipid synthesis in intact cells.39

Overall, luteolin may modulate multiple cell signaling pathways and target genes in breast cancer cells. These altered pathways lead to cell cycle arrest, apoptosis, and inhibition of cell growth, migration, and epithelial mesenchymal trans-differentiation (Fig. 2).

Luteolin modulates the signaling pathways and inhibits the growth and migration as well as promotes apoptosis of breast cancer cells.
Fig. 2  Luteolin modulates the signaling pathways and inhibits the growth and migration as well as promotes apoptosis of breast cancer cells.

Luteolin affects the effects of therapeutic drugs on breast cancer

Luteolin enhances the effects of therapeutic drugs on breast cancer

Several studies have provided evidence that luteolin can be used as a chemosensitizer for antitumor agents.63–68 Luteolin administered at doses less than 100 µM reverses tumor resistance of 4T1 and MCF-7 cells to doxorubicin and promotes death of tumor cells under hypoxia in vitro, although it has only slight effect on cell growth and cytotoxicity of doxorubicin under normoxia. The same was found in 4T1 and MCF-7 bearing mice.64 In these models, luteolin suppressed glycolytic flux but did not affect glucose uptake, the P-glycoprotein, antioxidative enzymes under hypoxia in vitro, or the intratumor doxorubicin level in vivo associated with increased and decreased activity of SOD and CAT in serum and in tumor, respectively.64 The combination of celecoxib and luteolin induced synergistic and inhibitory effects on the growth of cancer cells in vivo via Akt inactivation and ERK signaling inhibition in MCF-7 and MCF7/HER18 cells and via Akt inactivation and ERK signaling activation in MDA-MB-231 and SkBr3 cells.65,66

Luteolin reduces drug-resistance of human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression.69 Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3.70 These studies suggested that luteolin may enhance the effect of chemotherapeutic drugs on breast cancer by reducing drug resistance and promoting apoptotic effects and inhibition of breast cancer cell growth.

Low doses of luteolin protect breast cancer cells from cytotoxicity of therapeutic drugs

In a study by Sato et al.71 luteolin was found to have biphasic effects on viability of the human breast cancer cell line MCF-7. Luteolin at low concentrations, as low as 10 µM, was shown to protect the MCF-7 cells from doxorubicin toxicity, while in contrast, it inhibited cell viability at higher concentrations (>30 µM). Luteolin at 10 µM also attenuated doxorubicin-induced cytotoxicity in the presence of the ER antagonist ICI 182 780 and in the MDA-MB-453 human breast cancer cell line. Luteolin reduced doxorubicin-induced ROS generation and increased the antiapoptotic protein Bcl-2 levels in MCF-7 cells treated with doxorubicin. This may contribute to the ameliorating effects of luteolin on doxorubicin-induced cytotoxicity of MCF-7 cells.71 Therefore, the dosage of luteolin is a critical factor for determining its effects on breast cancer.

Current challenges and future research directions

Breast cancer is a complex disease with a large degree of inter- and intratumoral heterogeneity and personalized therapy should be assumed for cure.72–74 Although ER, PR, HER-2 and Ki-67 have been used for molecular classification of breast cancer and have achieved good outcomes, numerous subtypes of breast cancer have been identified based on novel molecular biomarkers,75 this surely will lead to better understanding and cure of breast cancer in the future. On the other hand, the corresponding therapeutic drugs should also be developed.

The inhibitory effects and underlying mechanisms of luteolin on breast cancer can be investigated when combined with traditional endocrine therapy, chemotherapy, and/or targeted therapy for the current and new molecular subtypes. The efficacy of luteolin in clinical treatment of breast cancer remains to be determined. It is also worthy of investigating whether luteolin is useful in male breast cancer and functional in novel personalized therapeutic approaches such as genomics-based therapies and immunity-based therapies.76–78

Conclusion

Luteolin is active in inhibiting the proliferation, progression and metastasis of breast cancer in a dose-dependent manner through suppressing cell cycles, inducing apoptosis, and inhibiting migration and EMT of breast cancer cells. These effects of luteolin are achieved through multiple signaling pathways, such as Notch, PI3K/Akt, MAPK/ERK1/2, EGFR, and NF-κB (Fig. 2).

Future research directions

Numerous studies have supported that luteolin is a promising drug for breast cancer therapy. To push its clinical use, several issues need to be addressed and solved in the future, including (1) determining the efficacy of luteolin combined with traditional endocrine therapy, chemotherapy, and /or targeted therapy for the current and new molecular subtypes on breast cancer, (2) clinical research on the efficacy of luteolin in treatment of several subtypes of breast cancer, (3) determining whether luteolin is useful in male breast cancer, and (4) determining if luteolin is functional in novel personalized therapeutic approaches such as genomics-based therapies and immunity-based therapies.

Abbreviations

AEG-1: 

astrocyte elevated gene 1

AKT: 

protein kinase B

AP-1: 

activator protein-1

CAT: 

catalase

DR5: 

death receptor 5

EGFR/HER: 

epidermal growth factor receptor

EMT: 

epithelial mesenchymal transition

ER: 

estrogen Receptor

ERK: 

extracellular signal-regulated kinase

ESP: 

estrogen signaling pathway

FAS: 

fatty acid synthase

JNK: 

Jun N-terminal kinase

KDR: 

vascular endothelial growth factor receptor 2

MAPK: 

mitogen-activated protein kinase

MMP: 

matrix metalloproteinase

NF-κB: 

nuclear factor-kappa B

PARP: 

poly ADP-ribose polymerase

PI3K: 

phosphatidylinositol 3-kinase

PKC: 

protein kinase C

PLK-1: 

polo-like kinase 1

PR: 

progesterone receptor

ROS: 

reactive oxygen species

SOD: 

superoxide dismutase

STAT: 

signal transducers and activators of transcription

TNBC: 

triple-negative breast cancer

TNFα: 

tumor necrosis factor alpha

TPL2: 

tumor progression locus 2

VEGF: 

vascular endothelial growth factor

VRK1: 

vaccinia-related kinase 1

Declarations

Acknowledgement

This work was supported by the Natural Science Foundation of Hubei Province, China (Grant# 2016CFB530), the Faculty Development Foundation of Hubei University of Medicine (Grant# 2014QDJZR01), the Science and Technology Research Project of Health and Family Planning Commission of Hubei Province (WJ2017Q038), and the Hubei Provincial Department of Education (Q20172104).

Conflict of interest

The authors have no conflict of interest related to this publication.

Authors’ contributions

Wrote the manuscript and provided funds (YW, JW, and XGu); wrote the manuscript (XGo and XW); revised the manuscript for important intellectual content (XGu); contributed equally to the work and should be regarded as co-first authors (YW, JW).

References

  1. Kocic B, Kitic D, Brankovic S. Dietary flavonoid intake and colorectal cancer risk: Evidence from human population studies. J BUON 2013;18:34-43
  2. Neuhouser ML. Dietary flavonoids and cancer risk: Evidence from human population studies. Nutr Cancer 2004;50:1-7 View Article
  3. Knekt P, Jarvinen R, Seppanen R, Hellovaara M, Teppo L, Pukkala E. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol 1997;146:223-230 View Article
  4. Wright ME, Mayne ST, Stolzenberg-Solomon RZ, Li Z, Pietinen P, Taylor PR. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol 2004;160:68-76 View Article
  5. Ross JA, Kasum CM. Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002;22:19-34 View Article
  6. Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 2008;8:634-646 View Article
  7. Chan TS, Galati G, Pannala AS, Rice-Evans C, O’Brien PJ. Simultaneous detection of the antioxidant and pro-oxidant activity of dietary polyphenolics in a peroxidase system. Free Radic Res 2003;37:787-794 View Article
  8. Theoharides TC, Stewart JM, Hatziagelaki E, Kolaitis G. Brain “fog,” inflammation and obesity: Key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci 2015;9:225 View Article
  9. Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Wozniak K. Luteolin as an anti-inflammatory and neuroprotective agent: A brief review. Brain Res Bull 2015;119:1-11 View Article
  10. Ye T, Su J, Huang C, Yu D, Dai S, Huang X. Isoorientin induces apoptosis, decreases invasiveness, and downregulates VEGF secretion by activating AMPK signaling in pancreatic cancer cells. Onco Targets Ther 2016;9:7481-7492 View Article
  11. Song S, Su Z, Xu H, Niu M, Chen X, Min H. 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 Article
  12. Lin X, Wei J, Chen Y, He P, Lin J, Tan S. Isoorientin from Gypsophila elegans induces apoptosis in liver cancer cells via mitochondrial-mediated pathway. J Ethnopharmacol 2016;187:187-194 View Article
  13. Kittiratphatthana N, Kukongviriyapan V, Prawan A, Senggunprai L. Luteolin induces cholangiocarcinoma cell apoptosis through the mitochondrial-dependent pathway mediated by reactive oxygen species. J Pharm Pharmacol 2016;68:1184-1192 View Article
  14. Nazaruk J, Galicka A. The influence of selected flavonoids from the leaves of Cirsium Palustre (L.) scop. On collagen expression in human skin fibroblasts. Phytother Res 2014;28:1399-1405 View Article
  15. Seelinger G, Merfort I, Wolfle U, Schempp CM. Anti-carcinogenic effects of the flavonoid luteolin. Molecules 2008;13:2628-2651 View Article
  16. Dia VP, Pangloli P. Epithelial-to-mesenchymal transition in paclitaxel-resistant ovarian cancer cells is downregulated by luteolin. J Cell Physiol 2017;232:391-401 View Article
  17. Palko-Labuz A, Sroda-Pomianek K, Uryga A, Kostrzewa-Suslow E, Michalak K. Anticancer activity of baicalein and luteolin studied in colorectal adenocarcinoma lovo cells and in drug-resistant LoVo/Dx cells. Biomed Pharmacother 2017;88:232-241 View Article
  18. Lee YJ, Lim T, Han MS, Lee SH, Baek SH, Nan HY. Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells. Oncol Rep 2017;37:1219-1226 View Article
  19. Zhang Q, Yang J, Wang J. Modulatory effect of luteolin on redox homeostasis and inflammatory cytokines in a mouse model of liver cancer. Oncol Lett 2016;12:4767-4772 View Article
  20. Pandurangan AK, Dharmalingam P, Sadagopan SK, Ganapasam S. Luteolin inhibits matrix metalloproteinase 9 and 2 in azoxymethane-induced colon carcinogenesis. Hum Exp Toxicol 2014;33:1176-1185 View Article
  21. Huang YT, Lee LT, Lee PP, Lin YS, Lee MT. Targeting of focal adhesion kinase by flavonoids and small-interfering RNAs reduces tumor cell migration ability. Anticancer Res 2005;25:2017-2025
  22. Kim HY, Jung SK, Byun S, Son JE, Oh MH, Lee J. Raf and PI3K are the molecular targets for the anti-metastatic effect of luteolin. Phytother Res 2013;27:1481-1488 View Article
  23. DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017;67:439-448 View Article
  24. Tang Y, Wang Y, Kiani MF, Wang B. Classification, treatment strategy, and associated drug resistance in breast cancer. Clin Breast Cancer 2016;16:335-343 View Article
  25. Taherian-Fard A, Srihari S, Ragan MA. Breast cancer classification: Linking molecular mechanisms to disease prognosis. Brief Bioinform 2015;16:461-474 View Article
  26. Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J. Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res 2015;5:2929-2943
  27. Reis-Filho JS, Pusztai L. Gene expression profiling in breast cancer: classification, prognostication, and prediction. Lancet 2011;378:1812-1823 View Article
  28. Gruver AM, Portier BP, Tubbs RR. Molecular pathology of breast cancer: The journey from traditional practice toward embracing the complexity of a molecular classification. Arch Pathol Lab Med 2011;135:544-557 View Article
  29. Andre F, Pusztai L. Molecular classification of breast cancer: Implications for selection of adjuvant chemotherapy. Nat Clin Pract Oncol 2006;3:621-632 View Article
  30. Parsa Y, Mirmalek SA, Kani FE, Aidun A, Salimi-Tabatabaee SA, Yadollah-Damavandi S. A review of the clinical implications of breast cancer biology. Electron Physician 2016;8:2416-2424 View Article
  31. Friend S, Royce M. The changing landscape of breast cancer: How biology drives therapy. Medicines (Basel) 2016;3:2 View Article
  32. Arnedos M, Vicier C, Loi S, Lefebvre C, Michiels S, Bonnefoi H. Precision medicine for metastatic breast cancer—limitations and solutions. Nat Rev Clin Oncol 2015;12:693-704 View Article
  33. Dai X, Cheng H, Bai Z, Li J. Breast cancer cell line classification and its relevance with breast tumor subtyping. J Cancer 2017;8:3131-3141 View Article
  34. Wang LM, Xie KP, Huo HN, Shang F, Zou W, Xie MJ. Luteolin inhibits proliferation induced by IGF-1 pathway dependent eralpha in human breast cancer MCF-7 cells. Asian Pac J Cancer Prev 2012;13:1431-1437 View Article
  35. Lee EJ, Oh SY, Sung MK. Luteolin exerts anti-tumor activity through the suppression of epidermal growth factor receptor-mediated pathway in MDA-MB-231 ER-negative breast cancer cells. Food Chem Toxicol 2012;50:4136-4143 View Article
  36. Attoub S, Hassan AH, Vanhoecke B, Iratni R, Takahashi T, Gaben AM. Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells. Eur J Pharmacol 2011;651:18-25 View Article
  37. Sui JQ, Xie KP, Xie MJ. Inhibitory effect of luteolin on the proliferation of human breast cancer cell lines induced by epidermal growth factor. Sheng Li Xue Bao 2016;68:27-34 View Article
  38. Sun DW, Zhang HD, Mao L, Mao CF, Chen W, Cui M. Luteolin inhibits breast cancer development and progression in vitro and in vivo by suppressing notch signaling and regulating mirnas. Cell Physiol Biochem 2015;37:1693-1711 View Article
  39. Brusselmans K, Vrolix R, Verhoeven G, Swinnen JV. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J Biol Chem 2005;280:5636-5645 View Article
  40. Lin CH, Chang CY, Lee KR, Lin HJ, Chen TH, Wan L. Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway. BMC Cancer 2015;15:958 View Article
  41. Wang L, Lee IM, Zhang SM, Blumberg JB, Buring JE, Sesso HD. Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am J Clin Nutr 2009;89:905-912 View Article
  42. Jiang Y, Xie KP, Huo HN, Wang LM, Zou W, Xie MJ. Inhibitory effect of luteolin on the angiogenesis of chick chorioallantoic membrane and invasion of breast cancer cells via downregulation of AEG-1 and MMP-2. Sheng Li Xue Bao 2013;65:513-518 View Article
  43. Lin D, Kuang G, Wan J, Zhang X, Li H, Gong X, Li H. Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of beta-catenin expression. Oncol Rep 2017;37:895-902 View Article
  44. Cook MT, Liang Y, Besch-Williford C, Hyder SM. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells. Breast Cancer (Dove Med Press) 2017;9:9-19 View Article
  45. Hong J, Fristiohady A, Nguyen CH, Milovanovic D, Huttary N, Krieger S. Apigenin and luteolin attenuate the breaching of MDA-MB231 breast cancer spheroids through the lymph endothelial barrier in vitro. Front Pharmacol 2018;9:220 View Article
  46. Rao PS, Satelli A, Moridani M, Jenkins M, Rao US. Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: Involvement of cell line-specific apoptotic mechanisms. Int J Cancer 2012;130:2703-2714 View Article
  47. Park SH, Ham S, Kwon TH, Kim MS, Lee DH, Kang JW. Luteolin induces cell cycle arrest and apoptosis through extrinsic and intrinsic signaling pathways in MCF-7 breast cancer cells. J Environ Pathol Toxicol Oncol 2014;33:219-231 View Article
  48. Alanazi IO, Khan Z. Understanding egfr signaling in breast cancer and breast cancer stem cells: Overexpression and therapeutic implications. Asian Pac J Cancer Prev 2016;17:445-453 View Article
  49. Han W, Lo HW. Landscape of egfr signaling network in human cancers: Biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett 2012;318:124-134 View Article
  50. Foley J, Nickerson NK, Nam S, Allen KT, Gilmore JL, Nephew KP. EGFR signaling in breast cancer: Bad to the bone. Semin Cell Dev Biol 2010;21:951-960 View Article
  51. Kumar S, Sharma AR, Sharma G, Chakraborty C, Kim J. PLK-1: Angel or devil for cell cycle progression. Biochim Biophys Acta 2016;1865:190-203 View Article
  52. Kumar S, Kim J. PLK-1 targeted inhibitors and their potential against tumorigenesis. Biomed Res Int 2015;2015:705745 View Article
  53. Markaverich BM, Shoulars K, Rodriguez MA. Luteolin regulation of estrogen signaling and cell cycle pathway genes in MCF-7 human breast cancer cells. Int J Biomed Sci 2011;7:101-111
  54. Nordeen SK, Bona BJ, Jones DN, Lambert JR, Jackson TA. Endocrine disrupting activities of the flavonoid nutraceuticals luteolin and quercetin. Horm Cancer 2013;4:293-300 View Article
  55. Ijichi N, Ikeda K, Horie-Inoue K, Inoue S. FOXP1 and estrogen signaling in breast cancer. Vitam Horm 2013;93:203-212 View Article
  56. Renoir JM, Marsaud V, Lazennec G. Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol 2013;85:449-465 View Article
  57. Brufsky AM, Dickler MN. Estrogen receptor-positive breast cancer: Exploiting signaling pathways implicated in endocrine resistance. Oncologist 2018;23:528-539 View Article
  58. Kim JE, Son JE, Jang YJ, Lee DE, Kang NJ, Jung SK. Luteolin, a novel natural inhibitor of tumor progression locus 2 serine/threonine kinase, inhibits tumor necrosis factor-alpha-induced cyclooxygenase-2 expression in JB6 mouse epidermis cells. J Pharmacol Exp Ther 2011;338:1013-1022 View Article
  59. Ferriola PC, Cody V, Middleton E. Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships. Biochem Pharmacol 1989;38:1617-1624 View Article
  60. Sourvinos G, Tsatsanis C, Spandidos DA. Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 1999;18:4968-4973 View Article
  61. Kim YS, Kim SH, Shin J, Harikishore A, Lim JK, Jung Y. Luteolin suppresses cancer cell proliferation by targeting vaccinia-related kinase 1. PloS One 2014;9:e109655 View Article
  62. Lupu R, Menendez JA. Pharmacological inhibitors of fatty acid synthase (FASN)—catalyzed endogenous fatty acid biogenesis: A new family of anti-cancer agents?. Curr Pharm Biotechnol 2006;7:483-493 View Article
  63. Amin AR, Wang D, Zhang H, Peng S, Shin HJ, Brandes JC. Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: Potential role of p53. J Biol Chem 2010;285:34557-34565 View Article
  64. Du GJ, Song ZH, Lin HH, Han XF, Zhang S, Yang YM. Luteolin as a glycolysis inhibitor offers superior efficacy and lesser toxicity of doxorubicin in breast cancer cells. Biochem Biophys Res Commun 2008;372:497-502 View Article
  65. Jeon YW, Suh YJ. Synergistic apoptotic effect of celecoxib and luteolin on breast cancer cells. Oncol Rep 2013;29:819-825 View Article
  66. Jeon YW, Ahn YE, Chung WS, Choi HJ, Suh YJ. Synergistic effect between celecoxib and luteolin is dependent on estrogen receptor in human breast cancer cells. Tumour Biol 2015;36:6349-6359 View Article
  67. Baskar AA, Ignacimuthu S, Michael GP, Al Numair KS. Cancer chemopreventive potential of luteolin-7-O-glucoside isolated from Ophiorrhiza mungos linn. Nutr Cancer 2011;63:130-138 View Article
  68. Lin YS, Tsai PH, Kandaswami CC, Cheng CH, Ke FC, Lee PP. Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells. Cancer Sci 2011;102:1829-1839 View Article
  69. Tu SH, Ho CT, Liu MF, Huang CS, Chang HW, Chang CH. Luteolin sensitises drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem 2013;141:1553-1561 View Article
  70. Yang MY, Wang CJ, Chen NF, Ho WH, Lu FJ, Tseng TH. Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3. Chem Biol Interact 2014;213:60-68 View Article
  71. Sato Y, Sasaki N, Saito M, Endo N, Kugawa F, Ueno A. Luteolin attenuates doxorubicin-induced cytotoxicity to MCF-7 human breast cancer cells. Biol Pharm Bull 2015;38:703-709 View Article
  72. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70 View Article
  73. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012;486:346-352 View Article
  74. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA. Molecular portraits of human breast tumours. Nature 2000;406:747-752 View Article
  75. Yeo SK, Guan JL. Breast cancer: Multiple subtypes within a tumor?. Trends Cancer 2017;3:753-760 View Article
  76. Fentiman IS. The biology of male breast cancer. Breast 2018;38:132-135 View Article
  77. Ruddy KJ, Winer EP. Male breast cancer: Risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol 2013;24:1434-1443 View Article
  78. Guerriero JL, Sotayo A, Ponichtera HE, Castrillon JA, Pourzia AL, Schad S. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 2017;543:428-432 View Article
Copyright © 2018 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Exploratory Research in Pharmacology
  • pISSN 2993-5121
  • eISSN 2572-5505

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2636374
  • Visits today : 2367
Back to Top

Luteolin: Anti-breast Cancer Effects and Mechanisms

Ying Wang, Jing Wang, Xing Gong, Xinxuan Wen, Xinsheng Gu
  • Reset Zoom
  • Download TIFF