Anticancer effect of the letrozole-quercetin combinationmediated by FOXOs and estrogen receptors in breast cancercells.

Anticancer effect of the letrozole-quercetin combinationmediated by FOXOs and estrogen receptors in breast cancercells.

T: Breast cancer is the most common malign tumor among women in the world and is the main lineage of cancer deaths due to its susceptibility to metastasis. Letrozole is used as an aromatase inhibitor and as anti-estrogenic, utilized to cure the breast cancer. Quercetin is a powerful antioxidant known as free radical scavenger, an important flavonoid. The current study was performed to examine the mechanism of action of the combination letrozole and quercetin in human breast cancer cells and to investigate the efficacy of letrozole and quercetin in breast cancer cells.Human breast cancer cells (MCF-7 and MDA-MB-231) were incubated with letrozole (10nM) and/or quercetin (5ng/mL). Cell proliferation of letrozole and quercetin in breast cancer cell lines was measured by MTT. Western blotting and qPCR were practiced to measure the protein and gene expression levels of ER-α, ER-β, Bax, Bcl-2, Foxo1, Foxo3, VEGF, Akt. Results from the study showed that letrozole and quercetin combination inhibited cell growth in MCF-7 and MDA-MB-231 cells and induced mitochondrial apoptosis. Letrozole and quercetin combination therapy may provide contributions to the development of new therapeutic drugs as an effective treatment approach for breast cancer patients.

___

  • [1] Klonowska K, Kluzniak W, Rusak B, Jakubowska A, Ratajska M et al. The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population. Oncotarget. 2017; 8(44): 76357–76374. [CrossRef]
  • [2] Jandial DD, Krill LS, Chen L, Wu C, Ke Y, et al. Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. Molecules. 2017; 22(3): 462. [CrossRef]
  • [3] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2): 87–108. [CrossRef]
  • [4] Smigal C, Jemal A, Ward E, Cokkinides V, Smith R, et al. Trends in Breast Cancer by Race and Ethnicity: Update 2006. CA Cancer J Clin. 2006; 56(3): 168–183. [CrossRef]
  • [5] Holleczek B, Arndt V, Stegmaier C, Brenner H. Trends in breast cancer survival in Germany from 1976 to 2008—A period analysis by age and stage. Cancer Epidemiol. 2011; 35(5): 399–406. [CrossRef]
  • [6] Howlader M, Heaton N, Rela M. Resection of liver metastases from breast cancer: Towards a management guideline. Int J Surg. 2011; 9(4): 285–91. [CrossRef]
  • [7] Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Prabhakar J, et al. Clinical Breast Examination: Preliminary Results from a Cluster Randomized Controlled Trial in India. JNCI J Natl Cancer Inst. 2011; 103(19): 1476–1480. [CrossRef]
  • [8] Lichtenstein P, Holm N V, Verkasalo PK, Iliadou A, Kaprio J et al. Environmental and Heritable Factors in the Causation of Cancer — Analyses of Cohorts of Twins from Sweden, Denmark, and Finland. N Engl J Med. 2000; 343(2): 78–85. [CrossRef]
  • [9] Osborne C, Tripathy D. Aromatase Inhibitors: Rationale and Use in Breast Cancer. Annu Rev Med. 2004; 56(1): 103– 16. [CrossRef]
  • [10] Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB et al. Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17. JNCI J Natl Cancer Inst. 2005; 97(17): 1262–1271. [CrossRef]
  • [11] Fridlender M, Kapulnik Y, Koltai H. Plant derived substances with anti-cancer activity: from folklore to practice Vol. 6, Frontiers in Plant Science. 2015; p. 799. [CrossRef]
  • [12] Hashemzaei M, Delarami Far A, Yari A, Heravi RE, Tabrizian K et al. Anticancer and apoptosis‑inducing effects of quercetin in vitro and in vivo. Oncol Rep. 2017; 38(2): 819–828. [CrossRef]
  • [13] Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010; 70(2): 440-446. [CrossRef]
  • [14] Acidereli H, Turut FA, Cevik O. Acetylation of interferon regulatory factor-5 suppresses androgen receptor and downregulates expression of Sox2. Cell Biochem Funct. 2021.
  • [15] Cevik O, Turut FA, Acidereli H, Yildirim S. Cyclosporine-A induces apoptosis in human prostate cancer cells PC3 and DU145 via downregulation of COX-2 and upregulation of TGFβ. Turkish J Biochem. 2019; 44(1): 47-54. [CrossRef]
  • [16] Sakai M, Elhilali M, Papadopoulos V. The GnRH Antagonist Degarelix Directly Inhibits Benign Prostate Hyperplasia Cell Growth. Horm Metab Res. 2015; 47(12): 925-931. [CrossRef]
  • [17] Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma. Cancer. 1998; 83(6): 1142–1152. [CrossRef]
  • [18] Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM et al. Aromatase Cytochrome P450, The Enzyme Responsible for Estrogen Biosynthesis. Endocr Rev. 1994; 15(3): 342–355. [CrossRef]
  • [19] Gadhwal MK, Patil S, D’Mello P, Joshi U, Sinha R et al. Synthesis, characterisation and antitumour activity of some quercetin analogues. Indian J Pharm Sci 2013; 75(2): 233–237. [CrossRef]
  • [20] Formica J V, Regelson W. Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol. 1995; 33(12): 1061–1080. [CrossRef]
  • [21] Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998; 16(2): 453–461. [CrossRef]
  • [22] Chi-Chen Y, Huang H-W, Wu Y-C, Chung C-C, Yuan S-S et al. Antioxidant Potential of Solvent Partitioned Extraction from Aqueous Extract of Gracilaria Tenuistipitata. Curr Org Chem. 2015; 19: 39–44. [CrossRef]
  • [23] Erlund I. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivties, bioavailability, and epidemiology. Nutr Res.2004; 24: 851–874. [CrossRef]
  • [24] Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S et al. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med. 2011; 2011: 591356. [CrossRef]
  • [25] Choi J-A, Kim J-Y, Lee J-Y, Kang C-M, Kwon H-J et al. Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol. 2001; 19(4): 837–44. [CrossRef]
  • [26] Chou C-C, Yang J-S, Lu H-F, Ip S-W, Lo C et al. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharm Res. 2010; 33(8): 1181–1191. [CrossRef]
  • [27] Adrain C, Martin S. The mitochondrial apoptosome: A killer unleashed by the cytochrome seas. Trends Biochem Sci. 2001; 26: 390–397. [CrossRef]
  • [28] Chien S-Y, Wu Y-C, Chung J-G, Yang J-S, Lu H-Fn et al. Quercetin-induced apoptosis acts through mitochondrialand caspase-3-dependent pathways in human breast cancer MDA-MB-231 cells. Hum Exp Toxicol. 2009; 28(8): 493– 503. [CrossRef]
  • [29] Van Der Woude H, Ter Veld MGR, Jacobs N, Van Der Saag PT, Murk AJ et al. The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor. Mol Nutr Food Res. 2005; 49(8): 763-771. [CrossRef]
  • [30] Bulzomi P, Galluzzo P, Bolli A, Leone S, Acconcia F, Marino M. The pro-apoptotic effect of quercetin in cancer cell lines requires ERβ-dependent signals. J Cell Physiol. 2012; 227: 1891-1898.
  • [31] Ranganathan S, Halagowder D, Sivasithambaram ND. Quercetin suppresses twist to induce apoptosis in MCF-7 breast cancer cells. PLoS One. 2015; 10(10): e0141370. [CrossRef]
  • [32] van Duursen MB, Nijmeijer SM, de Morree ES, de Jong PC, van den Berg M. Genistein induces breast cancerassociated aromatase and stimulates estrogen-dependent tumor cell growth in in vitro breast cancer model. Toxicology. 2011; 289(2-3): 67-73.
  • [33] Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WG. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis. 2008; 29(11): 2162-2168.
  • [34] Bullock M. FOXO factors and breast cancer: Outfoxing endocrine resistance. Endocrine-Related Cancer. 2016; 23 (2): R113-30. [CrossRef]
  • [35] Zhang Y, Gan B, Liu D, Paik JH. FoxO family members in cancer. Cancer Biol Ther. 2011; 12 (4): 253-259. [CrossRef]
  • [36] Schmitt-Ney M, Camussi G. The PAX3-FOXO1 fusion protein present in rhabdomyosarcoma interferes with normal FOXO activity and the TGF-β pathway. PLoS One. 2015; 10 (3): e0121474. [CrossRef]
  • [37] Morelli C, Lanzino M, Garofalo C, Maris P, Brunelli E et al. Akt2 Inhibition Enables the Forkhead Transcription Factor FoxO3a To Have a Repressive Role in Estrogen Receptor α Transcriptional Activity in Breast Cancer Cells. Mol Cell Biol. 2010; 30(3): 857-870. [CrossRef]
  • [38] Lv Y, Song S, Zhang K, Gao H, Ma R. CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells. PLoS One. 2013; 8(12): e83312. [CrossRef]
  • [39] Tokunaga E, Hisamatsu Y, Tanaka K, Yamashita N, Saeki H et al. Molecular mechanisms regulating the hormone sensitivity of breast cancer. Cancer Science. 2014; 105(11): 1377-83. [CrossRef] [40] Trinh XB, Tjalma WAA, Vermeulen PB, Van Den Eynden G, Van Der Auwera I et al. The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer. Br J Cancer. 2009; 100(6):971-8. [CrossRef]
  • [41] Dellinger MT, Brekken RA. Phosphorylation of Akt and ERK1/2 is required for VEGF-A/VEGFR2-induced proliferation and migration of lymphatic endothelium. PLoS One 2011; 6(12): e28947. [CrossRef]
  • [42] Zhu C, Qi X, Chen Y, Sun B, Dai Y et al. PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1- induced VEGF-C upregulation in breast cancer. J Cancer Res Clin Oncol. 2011; 137(11): 1587-94. [CrossRef]
  • [43] Kong L, Wu K, Lin H. Inhibitory effects of quercetin on angiogenesis of experimental mammary carcinoma. Chinese J Clin Oncol. 2005; 16(12): 1605-1614. [CrossRef]
  • [44] Li F, Bai Y, Zhao M, Huang L, Li S et al. Quercetin inhibits vascular endothelial growth factor-induced choroidal and retinal angiogenesis in vitro. Ophthalmic Res 2015; 53(3): 109-16. [CrossRef]
  • [45] Rivera AR, Castillo-Pichardo L, Gerena Y, Dharmawardhane S. Anti-breast cancer potential of quercetin via the AkT/AMPK/mammalian target of rapamycin (mTOR) signaling cascade. PLoS One 2016; 11(6): e0157251. [CrossRef]
  • [46] Li S, Qiao S, Zhang J, Li K. Quercetin Increase the Chemosensitivity of Breast Cancer Cells to Doxorubicin Via PTEN/Akt Pathway. Anticancer Agents Med Chem. 2015; 15(9): 1185-9. [CrossRef]
  • [47] Ezzati M, Yousefi B, Velaei K, Safa A. A review on anti-cancer properties of Quercetin in breast cancer. Life Sciences. 2020; 248: 117463. [CrossRef]
Journal of research in pharmacy (online)-Cover
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: Marmara Üniversitesi
Sayıdaki Diğer Makaleler

Development and in-vitro evaluation of chitosan chloridedecorated PLGA based polymeric nanoparticles ofnimesulide

Ceyda Tuba SENGEL-TÜRK, Bilge BAYRAM

Comparison of the in vitro efficacy of commercialbacteriophage cocktails and isolated bacteriophagevB_Pa01 against carbapenem resistant nosocomialPseudomonas aeruginosa

Banu KASKATEPE, Hilal Basak EROL

Development of 5-fluorouracil-loaded nano-sizedliposomal formulation by two methods: Strategies toenhance encapsulation efficiency of hydrophilic drugs

Tahir Emre YALÇIN, Aysel YILMAZ, Ceren YETGİN

Antioxidant, xanthine oxidase inhibitory and antibacterialactivities of selected galactogogue Thai medicinal plantwater and ethyl acetate extracts

Prapairat SEEPHONKAI, Natwipha MONGKOLSIRI, Wiranya THIABPHET, Rattanaphorn TRAISATHIT, Sutthira SEDLAK, Komgrit WONGPAKAM, Taweesak DHAMMARAJ, Aphidech SANGDEE

Anticancer effect of the letrozole-quercetin combinationmediated by FOXOs and estrogen receptors in breast cancercells.

Özge ÇEVİK, Yeter ÇİLESİZ

LC-MS/MS simultaneous determination of 37 bioactivecompounds in Bunium crassifolium Batt. and its biologicalactivities

Mehmet ÖZTÜRK, Abdulselam ERTAŞ, Nabila SOUILAH, Hamdi BENDIF, Zain ULLAH, Tarek HAMEL, Lakhdar DJARRI, Salah AKKAL, Kamel MEDJROUBI, Ahmed M. MUSTAFA

Comparative morphological and anatomical investigationson Corydalis caucasica subsp. abantensis Lidén andCorydalis integra Barbey & Fors.-Major (Papaveraceae)from Turkey

Bülent OLCAY, Şükran KÜLTÜR

Comparison of the apoptotic effects of bortezomib using2D and 3D co-culture models of THP-1 derived macrophageand A549 lung cancer

Miriş DİKMEN, Zerrin CANTÜRK, Selin ENGÜR ÖZTÜRK, Elif KAYA TİLKİ

Lenalidomide beneficially alters IL-16 methylation statusand IL-16 levels under rotenone insult in N9 cells

Fatma Nihan CANKARA, Zülfinaz Betül ÇELİK, Caner GÜNAYDIN

Nephroprotective effect of ethanol extract of Sonchusarvensis L. leaves in gentamicin-piroxicam induced ratrenal failure

Nova SULISKA, Mefani PRAVISKA, Neng Fisheri KURNIATI, Elin Yulinah SUKANDAR