Maggi Federica, Morelli Maria Beatrice, Aguzzi Cristina, Zeppa Laura, Nabissi Massimo, Polidori Carlo, Santoni Giorgio, Amantini Consuelo
School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
School of Pharmacy, University of Camerino, Camerino, Italy.
Front Mol Biosci. 2023 Feb 15;10:1129202. doi: 10.3389/fmolb.2023.1129202. eCollection 2023.
Calcium flux is the master second messenger that influences the proliferation-apoptosis balance. The ability of calcium flux alterations to reduce cell growth makes ion channels interesting targets for therapy. Among all, we focused on transient receptor potential vanilloid 1, a ligand-gated cation channel with selectivity for calcium. Its involvement in hematological malignancies is poorly investigated, especially in the field of chronic myeloid leukemia, a malignancy characterized by the accumulation of immature cells. FACS analysis, Western blot analysis, gene silencing, and cell viability assay were performed to investigate the activation of transient receptor potential vanilloid 1, by N-oleoyl-dopamine, in chronic myeloid leukemia cell lines. We demonstrated that the triggering of transient receptor potential vanilloid 1 inhibits cell growth and promotes apoptosis of chronic myeloid leukemia cells. Its activation induced calcium influx, oxidative stress, ER stress, mitochondria dysfunction, and caspase activation. Interestingly, a synergistic effect exerted by N-oleoyl-dopamine and the standard drug imatinib was found. Overall, our results support that transient receptor potential vanilloid 1 activation could be a promising strategy to enhance conventional therapy and improve the management of chronic myeloid leukemia.
钙流是影响增殖-凋亡平衡的主要第二信使。钙流改变降低细胞生长的能力使离子通道成为有吸引力的治疗靶点。其中，我们重点关注瞬时受体电位香草酸亚型1，一种对钙具有选择性的配体门控阳离子通道。其在血液系统恶性肿瘤中的作用研究较少，尤其是在慢性髓性白血病领域，这是一种以未成熟细胞积累为特征的恶性肿瘤。进行了流式细胞术分析、蛋白质免疫印迹分析、基因沉默和细胞活力测定，以研究N-油酰多巴胺对慢性髓性白血病细胞系中瞬时受体电位香草酸亚型1的激活作用。我们证明，瞬时受体电位香草酸亚型1的激活可抑制慢性髓性白血病细胞的生长并促进其凋亡。其激活诱导钙内流、氧化应激、内质网应激、线粒体功能障碍和半胱天冬酶激活。有趣的是，发现N-油酰多巴胺与标准药物伊马替尼具有协同作用。总体而言，我们的结果支持瞬时受体电位香草酸亚型1的激活可能是增强传统治疗并改善慢性髓性白血病管理的一种有前景的策略。
