Thymoquinone synergizes with arsenic and interferon alpha to target human T-cell leukemia/lymphoma
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Elsevier Inc.
Abstract
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. © 2020 Elsevier Inc.
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Combination therapy, Leukemia, Lymphoma, Targeted therapy, Xenograft, Animals, Antineoplastic combined chemotherapy protocols, Apoptosis, Arsenic, Benzoquinones, Cell line, tumor, Cell survival, Drug synergism, Human t-lymphotropic virus 1, Humans, Interferon-alpha, Jurkat cells, Leukemia-lymphoma, adult t-cell, Membrane potential, mitochondrial, Mice, Mice, inbred nod, Mice, scid, Time factors, Xenograft model antitumor assays, Alpha interferon, Arsenic derivative, Caspase 3, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, Protein bax, Protein bcl 2, Protein p53, Thymoquinone, X linked inhibitor of apoptosis, Antineoplastic agent, Benzoquinone derivative, Animal experiment, Animal model, Animal tissue, Antineoplastic activity, Article, C91 cell line, Cell cycle parameters, Cell population, Cell viability, Cem cell line, Clinical effectiveness, Concentration response, Controlled study, Down regulation, Drug potentiation, Flow cytometry, Human, Human cell, Human t-lymphotropic virus 1-transformed cell line, Hut 102 cell line, In vitro study, In vivo study, Jurkat cell line, Mitochondrial membrane potential, Mouse, Nod scid mouse, Nonhuman, Protein cleavage, Randomized controlled trial, Real time polymerase chain reaction, Staining, T cell leukemia, T cell lymphoma, Tumor volume, Upregulation, Western blotting, Animal, Drug effect, Drug screening, Isolation and purification, Nonobese diabetic mouse, Pathology, Scid mouse, Time factor, Tumor cell line