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Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study

Yıl 2023, Cilt: 27 Sayı: 3, 1270 - 1288, 28.06.2025

Tuğba Erkmen Halil Ateş , A. Semra Koçtürk

Öz

Acute myeloid leukemia (AML) is a form of acute leukemia with the highest incidence and the
lowest overall survival rates. Insufficiency of targeting leukemia stem cells (LSC) is the main obstacle that causes
drug resistance and relapse in AML. Another important problem is chemotherapeutics’ toxicity. Developing a
combination, including well-known chemotherapeutics in lower dose and new agent that have capacity to target
LSC may be more reliable and practical way to overcome these limitations. Previously, we found that Casticin
polyphenol induces apoptosis in AML stem-like (KG1a) and parental (KG1) cell lines without affecting healthy
cell. Therefore, for the first time, we aimed to find synergistic combination of Daunorubicin (DNR) and Casticin
to target apoptosis in both LSC and leukemic blasts with less toxicity. Synergism of DNR-Casticin combinations
on KG1a, KG1, HL-60 cells were determined with MTT viability assay by Chou-Talalay method. The
apoptotic/necrotic effects of combinations were evaluated with Annexin V- PI kit by flow cytometry. Synergistic
combination of 0.25 µM DNR + 0.0625 µM Casticin (combination index, CI<1) decreased cell viability to 45.3%
and 63.2% in KG1a, KG1 cell lines, respectively. However, the combination-induced apoptosis (KG1a: 5 %; KG1:
5.8%) were not higher than 0.25 µM DNR-induced (KG1a: 9.4%; KG1: 8.1%) or 0.0625 µM Casticin-induced
(KG1a: 3.8%; KG1: 5.1%) apoptosis (p>0.05). Our study showed that synergistic combination of DNR-Casticin
causes important decrease in cell viability. Although we did not detect increase in apoptosis with the
combination, we presume that other cell death pathways may be included. The highest apoptosis was obtained
by the treatment of 2 µM Casticin alone in KG1a (21.7%), KG1 (26.5%), HL-60 (14.6%). Therefore, we think that
Casticin polyphenol might be the possible candidate for new targeted therapy studies for AML.

Anahtar Kelimeler

Acute myeloid leukemia apoptosis combination leukemia stem cell

Kaynakça

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Yıl 2023, Cilt: 27 Sayı: 3, 1270 - 1288, 28.06.2025

Tuğba Erkmen Halil Ateş , A. Semra Koçtürk

Öz

Kaynakça

  • [1] Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. New Eng J Med. 2015;373(12):1136-1152.
  • [2] Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. New Eng J Med. 1999;341(14):1051-1062.
  • [3] Economides MP, McCue D, Borthakur G, Pemmaraju N. Topoisomerase II inhibitors in AML: past, present, and future. Expert Opin Pharmacother. 2019;20(13):1637-1644.
  • [4] Hulst MB, Grocholski T, Neefjes JJ, van Wezel GP, Metsä-Ketelä M. Anthracyclines: biosynthesis, engineering and clinical applications. Nat Prod Rep. 2022;39(4):814-841.
  • [5] Carraway HE. Improving overall survival in older adults with acute myeloid leukemia: subpopulations matter. J Clin Oncol. 2018;32:3186-3188.
  • [6] Löwenberg B, Rowe JM. Introduction to the review series on advances in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2016;1:1.
  • [7] Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, Ravandi F. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11(2):1-25.
  • [8] Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood. 2017;12:1577.
  • [9] Khaldoyanidi SK, Hindoyan A, Stein A, Subklewe M. Leukemic Stem Cells as a Target for Eliminating Acute Myeloid Leukemia: Gaps in Translational Research. Rev Oncol Hematol. 2022;175:103710.
  • [10] Darwish NH, Mousa SA. Intrinsic targeting strategies against acute myeloid leukemic stem cells. Leuk Lymphoma. 2018;11:2535-2545.
  • [11] Taussig DC, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T, Lillington D, Oakervee H, Cavenagh J, Agrawal SG, Lister TA, Gribben JG, Bonnet D. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34- fraction. Blood. 2010;115(10):1976-1984.
  • [12] Bailly JD, Muller C, Jaffrézou JP. Lack of correlation between expression and function of P-Glycoprotein in acute myeloid leukemia cell lines. Leukemia. 1995;9(5):799-807.
  • [13] Zucchi R, Danesi R. Cardiac toxicity of antineoplastic anthracyclines. Curr Med Chem. 2003;3(2):151-171.
  • [14] Narezkina A, Narayan HK, Zemljic-Harpf AE. Molecular mechanisms of anthracycline cardiovascular toxicity. Clin Sci. 2021;135(10):1311-1332.
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  • [16] Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Patel JP. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016;127(12):1551-1558.
  • [17] Hanahan D. Rethinking the war on cancer. Lancet. 2014;9916:558-563.
  • [18] Testa U, Riccioni R. Deregulation of apoptosis in acute myeloid leukemia. Haematologica. 2007;1:81-94.
  • [19] Neophytou CM, Trougakos IP, Erin N, Papageorgis P. Apoptosis deregulation and the development of cancer multi-drug resistance. Cancers. 2021;13(17):4363.
  • [20] Krawiec K, Strzałka P, Czemerska M, Wiśnik A, Zawlik I, Wierzbowska A, Pluta A. Targeting apoptosis in AML: Where do we stand? Cancers. 2022;14(20):4995.
  • [21] Karsch-Bluman A, Feiglin A, Arbib E, Stern T, Shoval H, Schwob O, Benny O. Tissue necrosis and its role in cancer progression. Oncogene. 2019;38(11):1920-1935.
  • [22] Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17(7):395-417.
  • [23] Zheng Z, Zhang L, Hou X. Potential roles and molecular mechanisms of phytochemicals against cancer. Food Funct. 2022;13(18):9208-9225.
  • [24] Sharma E, Attri DC, Sati P, Dhyani P, Szopa A, Sharifi-Rad J, Cho WC. Recent updates on anticancer mechanisms of polyphenols. Front Cell Dev Biol. 2022;10:1005910.
  • [25] Mahbub AA, Le Maitre CL, Haywood-Small SL, McDougall GJ, Cross NA, Jordan-Mahy N. Differential effects of polyphenols on proliferation and apoptosis in human myeloid and lymphoid leukemia cell lines. Anticancer Agents Med Chem. 2013;10:1601-1613.
  • [26] Hu L, Cao D, Li Y, He Y, Guo K. Resveratrol sensitized leukemia stem cell-like KG-1a cells to cytokine-induced killer cells-mediated cytolysis through NKG2D ligands and TRAIL receptors. Cancer Biol Ther. 2012;7:516-526.
  • [27] Shen JK, Du HP, Yang M, Wang YG, Jin J. Casticin induces leukemic cell death through apoptosis and mitotic catastrophe. Ann Hematol. 2009;88(8):743-752.
  • [28] Jin J, Shen JK, Du HP, Yang M, Wang YG. Apoptosis was induced by casticin in acute myelocytic leukemia cells. Blood. 2008;112(11):3991.
  • [29] Righeschi C, Eichhorn T, Karioti A, Bilia AR, Efferth T. Microarray-based mRNA expression profiling of leukemia cells treated with the flavonoid, Casticin. Cancer Genomics Proteomics. 2012;9(3):143-151.
  • [30] Erkmen T, Serdar BS, Ateş H, Keskinoglu P, Kocturk S. Casticin: A Promising candidate to develop a stem cell targeted strategy in AML treatment. J Basic Clin Health Sci. 2020;4(3):297-304.
  • [31] Fox JL, MacFarlane M. Targeting cell death signaling in cancer: minimising ‘Collateral damage’. Br J Cancer. 2016;115:5–11.
  • [32] Liang Z, He Y, Hu X. Cardio-Oncology: Mechanisms, drug combinations, and reverse cardio-oncology. Int J Mol Sci. 2022;23(18):10617.
  • [33] Zhou J, Chng WJ. Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia. World J Stem Cells. 2014;6(4):473.
  • [34] Siveen KS, Uddin S, Mohammad RM. Targeting Acute Myeloid Leukemia Stem Cell Signaling by Natural Products. Mol Cancer. 2017;16(1):13.
  • [35] Long NA, Golla U, Sharma A, Claxton DF. Acute myeloid leukemia stem cells: Origin, characteristics, and clinical implications. Stem Cell Rev Rep. 2022;18:1211–1226.
  • [36] Huffman DH, Benjamin RS, Bachur NR. Daunorubicin metabolism in acute nonlymphocytic leukemia. Clin Pharm Therap. 1972;13(6):895-905.
  • [37] Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;12:1253-1261.
  • [38] Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nat Cancer. 1994;367(6464):645-648.
  • [39] Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M. Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells. 2015;9:1185.
  • [40] Tan Y, Wu Q, Zhou F. Targeting acute myeloid leukemia stem cells: Current therapies in development and potential strategies with new dimensions. Crit Rev Oncol Hematol. 2020;152:102993.
  • [41] Speth PAJ, Linssen PCM, Boezeman JBM, Wessels HMC, Haanen C. Leukemic cell and plasma daunomycin concentrations after bolus injection and 72 h infusion. Cancer Chemother Pharmacol. 1987;20(4):311-315.
  • [42] Camaggi CM, Comparsi R, Strocchi E, Testoni F, Angelelli B, Pannuti F. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study. Cancer Chemother Pharmacol. 1988;21(3):221-228.
  • [43] Muller C, Chatelut E, Gualano V, De Forni M, Huguet F, Attal M, Canal P, Laurent G. Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: Comparison of bolus administration and continuous infusion. Cancer Chemother Pharmacol. 1993;32(5):379-384.
  • [44] Alberts DS, Bachur NR, Holtzman JL. The pharmacokinetics of daunomycin in man. Clin Pharmacol Ther. 1971;12(1):96-104.
  • [45] Albini A, Festa MM, Baci D, Benedetto N, Gutmanska K, Macrì N, Noonan DM. An extract of olive oil wastewater enhances chemotherapy effects on breast cancer cells without exacerbating cardiovascular toxicity. Cancer Res J. 2022;82(12):4044-4044.
  • [46] Xue P, Zhang G, Zhang J, Ren L. Synergism of ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment. Phytomedicine. 2022;18(99):153998.
  • [47] Castañeda AM, Meléndez CM, Uribe D, Pedroza-Díaz J. Synergistic effects of natural compounds and conventional chemotherapeutic agents: recent insights for the development of cancer treatment strategies. Heliyon. 2022;24(6):e09519.
  • [48] Kluska M, Juszczak M, Żuchowski J, Stochmal A, Woźniak K. Effect of Kaempferol and its glycoside derivatives on antioxidant status of HL-60 cells treated with Etoposide. Molecules. 2022;27(2):333.
  • [49] Gheybi F, Alavizadeh SH, Rezayat SM, Zendedel E, Jaafari M. Chemotherapeutic activity of Silymarin combined with doxorubicin liposomes in 4T1 breast cancer cells. J Nanomed Res. 2019;4(1):29-34.
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Toplam 74 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Eczacılık ve İlaç Bilimleri (Diğer)
Bölüm Articles
Yazarlar

Tuğba Erkmen 0000-0002-3178-9150

Halil Ateş 0000-0002-0112-5505

A. Semra Koçtürk 0000-0001-7528-1845

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2023 Cilt: 27 Sayı: 3

Kaynak Göster

APA Erkmen, T., Ateş, H., & Koçtürk, A. S. (2025). Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study. Journal of Research in Pharmacy, 27(3), 1270-1288.
AMA Erkmen T, Ateş H, Koçtürk AS. Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study. J. Res. Pharm. Haziran 2025;27(3):1270-1288.
Chicago Erkmen, Tuğba, Halil Ateş, ve A. Semra Koçtürk. “Does Combination of DNR and Casticin Show Advantage in Favor of Apoptosis on AML Leukemia Stem-Like Cell Lines? A Preliminary Study”. Journal of Research in Pharmacy 27, sy. 3 (Haziran 2025): 1270-88.
EndNote Erkmen T, Ateş H, Koçtürk AS (01 Haziran 2025) Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study. Journal of Research in Pharmacy 27 3 1270–1288.
IEEE T. Erkmen, H. Ateş, ve A. S. Koçtürk, “Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study”, J. Res. Pharm., c. 27, sy. 3, ss. 1270–1288, 2025.
ISNAD Erkmen, Tuğba vd. “Does Combination of DNR and Casticin Show Advantage in Favor of Apoptosis on AML Leukemia Stem-Like Cell Lines? A Preliminary Study”. Journal of Research in Pharmacy 27/3 (Haziran 2025), 1270-1288.
JAMA Erkmen T, Ateş H, Koçtürk AS. Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study. J. Res. Pharm. 2025;27:1270–1288.
MLA Erkmen, Tuğba vd. “Does Combination of DNR and Casticin Show Advantage in Favor of Apoptosis on AML Leukemia Stem-Like Cell Lines? A Preliminary Study”. Journal of Research in Pharmacy, c. 27, sy. 3, 2025, ss. 1270-88.
Vancouver Erkmen T, Ateş H, Koçtürk AS. Does Combination of DNR and Casticin show advantage in favor of apoptosis on AML leukemia stem-like cell lines? A preliminary study. J. Res. Pharm. 2025;27(3):1270-88.