Background
Eflornithine(DFMO) inhibits polyamine biosynthesis by irreversible inhibition of ornithine decarboxylase(ODC). It is a chemotherapeutic protectant that blocks angiogenesis. Its biological half-life is 8 hours[1-2].
Eflornithine (0.5 mM DFMO;72h) sensitizes homologous recombination (HR)-Competent Ovarian Cancer Cells to Rucaparib [3]. Combination of Eflornithine (1 mM; 48 h) and Thymoquinone (TQ) significantly reduced cell viability and resulted in significant synergistic effects on apoptosis when compared to either Eflornithine or TQ alone in Jurkat cells [4]. Eflornithine (5 mM;72h) treatment leads to the accumulation of the cyclin-dependent kinase inhibitor p27(Kip1) protein and causes p27(Kip1)/Rb-coupled G (1) cell cycle arrest in MYCN-amplified NB tumor cells through a process that involves p27(Kip1) phosphorylation at residues Ser10 and Thr198[5].
Eflornithine (1% w/v in the drinking water; 48-72 h) alone markedly increases survival of pancreatic tumor-bearing mice in contrast with GW5074 across multiple dosing and tumor seeding strategies [6]. The Kras(G12D/+) mice fed Eflornithine at 0.1% and 0.2% in the diet showed a significant inhibition of pancreatic ductal adenocarcinoma (PDAC) incidence compared with mice fed control diet [7].
依氟鸟氨酸(Eflornithine, DFMO)是一种阻断血管生成的化疗保护剂。它通过不可逆地抑制鸟氨酸脱羧酶(ODC)抑制多胺的生物合成,其生物半衰期为8h[1-2]。
Eflornithine (0.5 mM DFMO;72h)使卵巢癌细胞对Rucaparib更加敏感[3]。在Jurkat细胞中,与Eflornithine或Thymoquinone (TQ)单独使用相比,Eflornithine (1 mM; 48 h)和TQ联合使用可显著降低细胞活力,并对凋亡产生显著的协同作用[4]。Eflornithine (5 mM;72h)处理导致周期蛋白依赖性激酶抑制剂p27(Kip1)蛋白的积累,并通过Ser10和Thr198磷酸化,在MYCN-amplified的NB肿瘤细胞中引起p27(Kip1)/Rb-coupled G(1)细胞周期阻滞[5]。
Eflornithine (1% w/v in the drinking water; 48-72 h)可显著提高胰腺荷瘤小鼠的存活率[6]。与对照组相比,饲粮中添加0.1%和0.2% Eflornithine的Kras(G12D/+)小鼠对胰腺导管腺癌(pancreatic ductal adencarcinoma, PDAC)发病有显著抑制作用[7]。
参考文献:
[1]. Drugs and Lactation Database (LactMed?) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006-. Eflornithine. 2021 Dec 20. PMID: 29999676.
[2]. Kang CN, Shah M, et,al. Hair Removal Practices: A Literature Review. Skin Therapy Lett. 2021 Sep;26(5):6-11. PMID: 34524781.
[3]. El Naggar O, Doyle B, et,al. Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells. Med Sci (Basel). 2022 May 26;10(2):28. doi: 10.3390/medsci10020028. PMID: 35736348; PMCID: PMC9230675.
[4]. Alhosin M, Razvi SSI, et,al. Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways. Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820947489. doi: 10.1177/1533033820947489. PMID: 32912061; PMCID: PMC7488875.
[5]. Koomoa DL, Geerts D, et,al. DFMO/eflornithine inhibits migration and invasion downstream of MYCN and involves p27Kip1 activity in neuroblastoma. Int J Oncol. 2013 Apr;42(4):1219-28. doi: 10.3892/ijo.2013.1835. Epub 2013 Feb 21. PMID: 23440295; PMCID: PMC3622674.
[6]. Nakkina SP, Gitto SB, et,al. DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment. Int J Mol Sci. 2021 Dec 7;22(24):13175. doi: 10.3390/ijms222413175. PMID: 34947972; PMCID: PMC8706739.
[7]. Mohammed A, Janakiram NB, et,al. Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling. Cancer Prev Res (Phila). 2014 Dec;7(12):1198-209. doi: 10.1158/1940-6207.CAPR-14-0176. Epub 2014 Sep 23. PMID: 25248858; PMCID: PMC4310684.
Protocol
| Cell experiment [1]: |
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Cell lines
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OVCAR5 and SKOV3 cells
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Preparation Method
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Cells were treated with 0.5 mM Eflornithine (DFMO) and rucaparib.
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Reaction Conditions
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0.5 mM Eflornithine ;72h
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Applications
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Eflornithine Sensitizes homologous recombination (HR)-Competent Ovarian Cancer Cells to Rucaparib.
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| Animal experiment [2]: |
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Animal models
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Pancreas of athymic (nu/nu) mice (Human pancreatic L3.6pl tumor model)
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Preparation Method
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Mice were treated for two weeks with control, GW5074 (1 mg/kg), Eflornithine (1% w/v) and Eflornithine + GW5074 after a week post orthotopic tumor cell implantation.
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Dosage form
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1% w/v Eflornithine in the drinking water; 48-72 h
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Applications
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Eflornithinealone markedly increases survival of pancreatic tumor-bearing mice in contrast with GW5074 across multiple dosing and tumor seeding strategies.
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参考文献:
[1]. El Naggar O, Doyle B, et,al. Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells. Med Sci (Basel). 2022 May 26;10(2):28. doi: 10.3390/medsci10020028. PMID: 35736348; PMCID: PMC9230675.
[2].Nakkina SP, Gitto SB, et,al. DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment. Int J Mol Sci. 2021 Dec 7;22(24):13175. doi: 10.3390/ijms222413175. PMID: 34947972; PMCID: PMC8706739.
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