Zeynep ÖZDEMİR, Erkan YURTCU, Yeşim KASAP KORKMAZ, Çağan ASPARUK, Oğuzhan AK, Doğa AKGÖR, Fulya ELMASTAŞ, Doğukan AKKUŞ, Dide AYSUN

Teobromin STI571'in Apoptotik Etkinliğini Artırır mı?

Amaç: Tirozin kinaza özgü bir inhibitör olan STI571 KML kemoterapisinde kullanılır. Diğer kemoterapötik ajanlara benzer şekilde, bazı hastalarda ilaç direnci ve intoksikasyon sebebiyle sınırlı bir etkinliğe sahiptir. Bu yüzden, çoğu kanser hastası kemoterapötik ajanın etkinliğini artırmak için günlük ek gıdalar ve bitkisel ekstraktları kullanır. Kakaonun bir metaboliti olan teobromin prooksidan etkilere sahiptir ve hücre içi sinyal yolaklarını düzenler. Çalışmamızın amacı birlikte ve ayrı ayrı kullanıldığında STI571 ve teobrominin K562 hücreleri üzerinde potansiyel apoptotik etkilerini göstermektir. Yöntem: STI571 ve teobrominin inhibitör konsantrasyonları MTT metoduyla belirlendi. Her iki ajan da hücrelere 48 saat süre ile tek başına ve birlikte olacak şekilde uygulandı. Kaspaz aktiviteleri kolorimetrik olarak belirlendi. Apoptoz ve nekroz akridin turuncusu/etidyum bromür boyaması ile değerlendirildi. p

Does Theobromine Increase the Apoptotic Effect of STI571?

Objective: STI571, a selective tyrosine kinase inhibitor is used in CML chemotherapy. It has limited effects in some cases due to drug resistance and intoxication as other chemotherapeutic agents. Thus, many cancer patients use dietary supplements and herbal extracts for increasing the effectiveness of chemotherapeutic agents. Theobromine, a metabolite of cacao has prooxidant effects and regulates intercellular signaling pathways. The aim of the study is to determine the potential apoptotic effects of STI571 and theobromine on K562 cells, when used alone and in combination. Methods: Inhibitory concentrations of STI571 and theobromine were determined by MTT method. Both agents were applied to the cells at 48 h time period alone and in combination. Caspase activities were assessed colorimetrically. Apoptosis and necrosis were evaluated by using acridine orange/ethidium bromide staining. p

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Nowell PC. Discovery of the Philadelphia chromosome: a personal perspective. J Clin Invest. 2007; 117:2033-5
Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000 96:3343-56
Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. European LeukemiaNet. Lancet 2007; 28;370:342-50
Latif R. Chocolate/cocoa and human health: a review. Neth J Med. 2013;71:63-8
Smit HJ and Blackburn RJ. Reinforcing effects of caffeine and theobromine as found in chocolate. Psychopharmacology (Berl) 2005; 181:101-6
Smit HJ, Gaffan EA, Rogers PJ, Methylxanthines are the psycho- pharmacologically Psychopharmacology (Berl) 2004; 176:412-9 constituents of chocolate.
Kamphuis J, Smits P, Thien T. Vascular effects of pentoxifylline in humans. J Cardiovasc Pharmacol. 1994; 24:648-54
Baskic D, Popovic S, Ristic P, Arsenijevic NN. Analysis of apoptosis cycloheximide-induced fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide. Cell Biol Int. 2006; 30:924-32
Morozova EV, Vlasova YY, Pryanishnikova MV, Lepik KV, Afanasyev BV. Efficacy of Dasatinib in a CML Patient in Blast Crisis with F317L Mutation: A Case Report and Literature Review. Biomark Insights. 2015; 8:10 (Suppl 3):43-7. doi: 10.4137/BMI.S22438
Kim J, Kim J, Shim J, Lee CY, Lee KW, Lee HJ. Cocoa phytochemicals: recent advances in molecular mechanisms on health. Crit Rev Food Sci Nutr. 2014;54:1458-72.
Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181-90
Muppidi JR, Tschopp J, Siegel RM. Life and death decisions: Secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity. 2004;21:461-5.
Cadoná FC, Machado AK, Azzolin VF, Barbisan F, Dornelles EB, Glanzner W, et al. Guaraná a richest caffeine food increase oxaliplatin sensitivity of colorectal HT-29 cells by apoptosis pathway modulation. Anticancer Agents Med Chem. 2015 DOI: 10.2174/1871520616666151217121138
Marques GM, Rasslan R, Belon AR, Carvalho JG, Felice Neto R, Rasslan S, et al. Pentoxifylline associated to hypertonic saline solution attenuates inflammatory process and apoptosis after intestinal ischemia/reperfusion in rats. Acta Cir Bras. 2014; 29:735-41.
Sugimoto N, Miwa S, Hitomi Y, Nakamura H, Tsuchiya H, Yachie A. Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal- regulated kinase, Akt/mammalian target of rapamycin kinase, and nuclear factor-kappa B. Nutr Cancer. 2014; 66:419-23.
Zhu J, Ding B, Li Y. Long-term effect of interferon-? combined with homoharringtonine on chronic myelogenous leukemia in chronic phase. Leuk Lymphoma. 2013; 54:1426-9.
Huang BT, Zeng QC, Zhao WH, Tan Y. Homoharringtonine contributes to imatinib sensitivity by blocking the EphB4/RhoA pathway in chronic myeloid leukemia cell lines. Med Oncol. 2014; 31:836.
Xu XH, Gan YC, Xu GB, Chen T, Zhou H, Tang JF, et al. Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/?-catenin axis. J Zhejiang Univ Sci B. 2012; 13:867-74.
Yan-lin Wei, Lei Xu, Yun Liang, Xiao-hua Xu, Xiao-ying Zhao. Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo Acta Pharmacologica Sinica 2009; 30: 451-7.