Gülsüm ABUŞOĞLU, Cengiz KOÇAK, Fatma KOÇAK, Bahadir OZTURK, Hüsamettin VATANSEV

CDDO-Me'nin Meme Kanseri Hücrelerindeki Etkilerinin Tamoxifen ve Docetaxel ile Karşılaştırılması

Amaç: Oleanolik asitten türetilen sentetik triterpenoidlerin, güçlü antiproliferatif ve antitümörojenik aktiviteye sahip oldukları bilinmektedir. Bu çalışmada, bir triterpenoid olan CDDO-Me'nin insan meme kanseri hücre hatları üzerindeki sitotoksik etkilerini, meme kanserinin rutin tedavisinde kullanılan Tamoxifen ve Docetaxel ile karşılaştırarak araştırmaktır. Materyal Metod: CDDO-Me, Docetaxel veTamoxifen’in sitotoksik etkilerini incelemek için meme kanseri hücreleri olarak MCF-7 ve MDA MB-231 hücre hatları tercih edildi. Her bir ilacın çeşitli dozları hücrelere uygulanarak sitotoksik etkileri xCELLigence cihazı ile belirlendi ve ilaçların IC50 değerleri belirlendi. IC50 dozlarıyla muamele edilen hücrelerden hücre blokları hazırlanarak, histolojik ve immünohistokimyasal boyama ile proliferasyon indeksi Ki-67 ve Cyclin D1, antiapoptotik Bcl-2 ve proapoptotik Bax protein ekspresyonları skorlandı. Bulgular: CDDO-Me, Docetaxel veTamoxifen her iki hücre hattında hücre canlılığını istatistiksel olarak önemli bir şekilde inhibe etti. CDDO-Me'nin Tamoxifen ve Docetaxel ile etkileri moleküler düzeyde karşılaştırıldığında, her iki hücre hattında da apopitoz yolağı açısından CDDO-Me’nin, Tamoxifen ve Docetaxel’e göre istatistiksel olarak daha etkili olduğu (p

Comparison of the Effects of CDDO-Me with Tamoxifen and Docetaxel on Breast Cancer Cells

PDF

___

[1] Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010;363(20):1938-48.
[2] Uray IP, Brown PH. Chemoprevention of hormone receptor-negative breast cancer: new approaches needed. Recent Results Cancer Res 2011;188:147-62.
[3] DeSantis C, Howlader N, Cronin KA, Jemal A. Breast cancer incidence rates in U.S. women are no longer declining. Cancer Epidemiol Biomarkers Prev 2011;20 (5):733-9.
[4] Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feurer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007; 356:1670-4.
[5] Cuzick J, DeCensi A, Arun B, Brown PH, Castiglione M, Dunn B, et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol 2011;12:496-503.
[6] Brown PH, Subbaramaiah K, Salmon AP, Baker R, Newman RA, Yang P, et al. Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid. Cancer Prev Res [Phila] 2008;1 (3):208-14.
[7] Borella R, Forti L, Gibellini L, De Gaetano A, De Biasi, Nasi M, et al. Synthesis and anticancer activity of CDDO and CDDO-Me, two derivatives of natural triterpenoids. Molecules 2019; 24:4097-117.
[8] Zhao Y, Huo M, Xu Z, Wang Y, Huang L. Nanoparticle delivery of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma. Biomaterials 2015;68:54-66.
[9] Ball MS, Shipman EP, Kim H, Liby KT, Pioli PA. CDDO-Me redirects activation of breast tumor associated macrophages. PLoS One 2016;11:e0149600.
[10] Wang XY, Zhang XH, Peng L, Liu Z, Yang YX, He ZX, et al. Bardoxolone methyl [CDDO-Me or RTA402] induces cell cycle arrest, apoptosis and autophagy via PI3K/Akt/mTOR and p38 MAPK/Erk1/2 signaling pathways in K562 cells. Am J Transl Res 2017; 9 (10):4652-72.
[11] Khurana N, Chandra PK, Kim H, Abdel-Mageed AB, Mondal D, Sikka SC. Bardoxolone-Methyl [CDDO-Me] suppresses androgen receptor and ıts splice-variant ar-v7 and enhances efficacy of enzalutamide in prostate cancer cells. Antioxidants [Basel] 2020; 9:68-86.
[12] Konopleva M, Contractor R, Kurinna SM, Chen W, Andreeff M, Ruvolo P. The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells. Leukemia 2005; 19:1350-4.
[13] Lapillonne H, Konopleva M, Tsao T, Gold D, McQueen T, Sutherland RL, et al. Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells. Cancer Res 2003; 63:5926-39.
[14] Lewis JH, Jadoul M, Block GA, Chin MP, Ferguson DA, Goldsberry A, et al. Effects of bardoxolone methyl on hepatic enzymes in patients with type 2 diabetes mellitus and stage 4 CKD. Clin Transl Sci 2021; 14:299-309.
[15] Ball MS, Bhandari R, Torres GM, Martyanov V, ElTanbouly MA, Archambaut K, et al. CDDO-Me alters the tumor microenvironment in estrogen receptor negative breast cancer. Sci Rep 2020;10:6560-70.
[16] Kanda H, Yamawaki K. Bardoxolone methyl: drug development for diabetic kidney disease. Clin Exp Nephrol 2020; 24:857-64.
[17] Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H, Seiden MV, et al. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol 2009; 63 (4):681-9.
[18] Hermann C, Lang S, Popp T, Hafner S, Steinritz D, Rump A, et al. Bardoxolone-Methyl [CDDO-Me] ımpairs tumor growth and ınduces radiosensitization of oral squamous cell carcinoma cells. Front Pharmacol 2020; 11:607580.
[19] Deeb D, Gao X, Liu YB, Gautam S. Inhibition of cell proliferation and induction of apoptosis by CDDO-Me in pancreatic cancer cells is ROS-dependent. J Exp Ther Oncol 2012; 10 (1):51-64.
[20] Gao X, Deeb D, Liu P, Liu Y, Arbab-Ali S, Dulchavsky SA, et al. Role of reactive oxygen species [ROS] in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells. J Exp Ther Oncol 2011; 9 (2):119-27.
[21] Tran K, Risingsong R, Royce D, Williams CR, Sporn MB, Liby K. The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice. Cancer Prev Res [Phila] 2012; 5 (5):726-34.
[22] Liby K, Risingsong R, Royce DB, Williams CR, Yore MM, Honda T, et al. Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268. Clin Cancer Res 2008;14:4556-63.
[23] Hyer ML, Croxton R, Krajewska M, Krajewski S, Kress CL, Lu M, et al. Synthetic triterpenoids cooperate with tumor necrosis factor-related apoptosis-inducing ligand to induce apoptosis of breast cancer cells. Cancer Res 2005;65:4799-808.
[24] Ling X, Konopleva M, Zeng Z, Ruvolo V, Stephens LC, Schober W, et al. The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling. Cancer Res 2007;67:4210-8.
[25] Kim EH, Deng CX, Sporn MB, Liby KT. CDDO-imidazolide induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells. Cancer Prev Res [Phila] 2011;4:425-34.
[26] Jeong SA, Kim IY, Lee AR, Yoon MJ, Cho H, Lee JS, et al. Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me-induced apoptosis in breast cancer cells. Oncotarget 2015;6:21173-92.
[27] Radushev D. GraphPad Prism Software v5.02.San Diego, CA, USA. 2008.
[28] Lee SH, Lee JK, Jin SM, Lee KC, Sohn JH, Chae SW, et al. Expression of cell-cycle regulators [cyclin D1, cyclin E,p27kip1, p57kip2] in papillary thyroid carcinoma. Otolaryngol Head Neck Surg 2010; 142, 332-337.
[29] Sessa F, Bonato M, Bisoni D, Ranzani GN, Capella C. Ki-ras and p53 gene mutations in pancreatic ductal carcinoma: a relationship with tumor phenotype and survival. Eur J Histochem 1998;42:67-76.
[30] Konopleva M, Zhang W, Shi YX, McQueen T, Tsao T, Abdelrahim M, et al. Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells. Mol Cancer Ther 2006; 5:317-28.