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Thymoquinone synergizes with arsenic and interferon alpha to target human T-cell leukemia/lymphoma.
Life Sciences ( IF 5.2 ) Pub Date : 2020-04-06 , DOI: 10.1016/j.lfs.2020.117639 Marwa Houssein 1 , Maamoun Fatfat 2 , Zeina Habli 2 , Nasab Ghazal 3 , Sara Moodad 4 , Hala Khalife 5 , Mahmoud Khalil 1 , Hala Gali-Muhtasib 6
Life Sciences ( IF 5.2 ) Pub Date : 2020-04-06 , DOI: 10.1016/j.lfs.2020.117639 Marwa Houssein 1 , Maamoun Fatfat 2 , Zeina Habli 2 , Nasab Ghazal 3 , Sara Moodad 4 , Hala Khalife 5 , Mahmoud Khalil 1 , Hala Gali-Muhtasib 6
Affiliation
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AIMS
To reduce the dose of arsenic used against human T-cell leukemia/lymphoma and to sensitize cells to drug treatment, we combined arsenic/interferon-alpha (As/IFN-α) with thymoquinone (TQ) in HTLV-I positive (HuT-102 and C91) and HTLV-1 negative (CEM and Jurkat) cell lines.
MAIN METHODS
Cells were treated with TQ, As/IFN-α and combinations. Trypan blue and flow cytometry were used to investigate viability and cell cycle effects. Annexin-V staining, rhodamine assay and western blotting were used to determine apoptosis induction and changes in protein expression. Efficacy of single drugs and combinations were tested in adult T-cell leukemia (HuT-102) mouse xenograft model.
KEY FINDINGS
TQ/As/IFN-α led to a more pronounced and synergistic time-dependent inhibitory effect on HTLV-I positive cells in comparison to As/IFN-α. While As/IFN-α combination was not effective against CEM or Jurkat cells, the triple combination TQ/As/IFN-α sensitized these two cell lines and led to a pronounced time-dependent inhibition of cell viability. TQ/As/IFN-α significantly induced apoptosis in all four cell lines and disrupted the mitochondrial membrane potential. Apoptosis was confirmed by the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), downregulation of Bcl-2 and XIAP and upregulation of Bax. TQ alone or in combination activated p53 in HTLV-1 positive cell lines. Strikingly, TQ/As/IFN-α resulted in a pronounced significant decrease in tumor volume in HuT-102 xenograft mouse model, as compared to separate treatments or double combination therapy.
SIGNIFICANCE
Our results suggest a strong potential for TQ to enhance the drug targeting effects of the standard clinical drugs As and IFN-α against CD4+ malignant T-cells.
中文翻译：
胸腺醌与砷和干扰素α协同作用，靶向人T细胞白血病/淋巴瘤。
目的为了减少用于人类T细胞白血病/淋巴瘤的砷剂量并使细胞对药物治疗敏感，我们将HTLV-1阳性（HuT -102和C91）和HTLV-1阴性（CEM和Jurkat）细胞系。主要方法用TQ，As /IFN-α及其混合物处理细胞。台盼蓝和流式细胞仪用于研究生存力和细胞周期的影响。Annexin-V染色，若丹明测定和western blotting用于确定细胞凋亡诱导和蛋白表达的变化。在成年T细胞白血病（HuT-102）小鼠异种移植模型中测试了单一药物及其组合的功效。主要发现与As /IFN-α相比，TQ / As /IFN-α对HTLV-1阳性细胞产生了更明显和协同的时间依赖性抑制作用。虽然As /IFN-α组合对CEM或Jurkat细胞无效，但三重组合TQ / As /IFN-α使这两个细胞系敏感，并导致明显的时间依赖性抑制细胞活力。TQ / As /IFN-α显着诱导所有四个细胞系的凋亡，并破坏了线粒体膜电位。凋亡通过胱天蛋白酶3和聚（ADP-核糖）聚合酶（PARP）的切割，Bcl-2和XIAP的下调以及Bax的上调来证实。TQ单独或联合使用可激活HTLV-1阳性细胞系中的p53。令人惊讶的是，与单独治疗或双重联合疗法相比，TQ / As /IFN-α在HuT-102异种移植小鼠模型中导致肿瘤体积明显减少。
更新日期：2020-04-06
中文翻译：
胸腺醌与砷和干扰素α协同作用，靶向人T细胞白血病/淋巴瘤。
目的为了减少用于人类T细胞白血病/淋巴瘤的砷剂量并使细胞对药物治疗敏感，我们将HTLV-1阳性（HuT -102和C91）和HTLV-1阴性（CEM和Jurkat）细胞系。主要方法用TQ，As /IFN-α及其混合物处理细胞。台盼蓝和流式细胞仪用于研究生存力和细胞周期的影响。Annexin-V染色，若丹明测定和western blotting用于确定细胞凋亡诱导和蛋白表达的变化。在成年T细胞白血病（HuT-102）小鼠异种移植模型中测试了单一药物及其组合的功效。主要发现与As /IFN-α相比，TQ / As /IFN-α对HTLV-1阳性细胞产生了更明显和协同的时间依赖性抑制作用。虽然As /IFN-α组合对CEM或Jurkat细胞无效，但三重组合TQ / As /IFN-α使这两个细胞系敏感，并导致明显的时间依赖性抑制细胞活力。TQ / As /IFN-α显着诱导所有四个细胞系的凋亡，并破坏了线粒体膜电位。凋亡通过胱天蛋白酶3和聚（ADP-核糖）聚合酶（PARP）的切割，Bcl-2和XIAP的下调以及Bax的上调来证实。TQ单独或联合使用可激活HTLV-1阳性细胞系中的p53。令人惊讶的是，与单独治疗或双重联合疗法相比，TQ / As /IFN-α在HuT-102异种移植小鼠模型中导致肿瘤体积明显减少。
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