Schcolnik-Cabrera Alejandro, Ramírez-Yautentzi Marisol, Soria-Castro Rodolfo, Chacón-Salinas Rommel, Morales-Bárcenas Rocío, Domínguez-Gómez Guadalupe, González-Fierro Aurora, Dueñas-González Alfonso, Chávez-Blanco Alma
Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB, Canada.
Division of Basic Research, National Institute of Oncology, Ave. San Fernando 22, 14080, Tlalpan, Mexico City, Mexico.
Med Oncol. 2025 Jul 24;42(9):371. doi: 10.1007/s12032-025-02941-9.
Mast cells (MC) play a crucial role in the tumor microenvironment (TME) by promoting tumor progression and immune evasion through the secretion of inflammatory mediators. Here, we investigate the impact of epigenetic reprogramming using a drug repurposing combination-hydralazine, a DNA methylation inhibitor, and valproate, a histone deacetylase inhibitor (HDACi)-on MC-cancer cell interactions. Human cancer cell lines (Ca Ski, MDA-MB-468, and A549) that secrete stem cell factor (SCF) were selected from a panel of tumor lines. The HMC-I MC line and the selected cancer cell lines were treated with hydralazine + valproate (HV) for 72 h, and viability assessed via trypan blue exclusion assay revealed consistent reduction across all lines. Conditioned medium (CM) from HV-treated MCs was applied to cancer cells, with MDA-MB-468 displaying resistance. CM from HV-treated cancer cells was then used to evaluate MC migration and chemotaxis, showing reduced mobility in MCs exposed to supernatants from Ca Ski and MDA-MB-468, but not A549. Flow cytometry analysis revealed that HV epigenetically suppressed the expression of pro-tumoral cytokines and MC chemoattractants, with ITAC being the only consistently upregulated cytokine. These findings demonstrate that pharmacological epigenetic reprogramming via HV modulates MC-driven tumor progression and reshapes the cytokine network, highlighting its potential as a novel immunoepigenetic therapeutic strategy in cancer.
肥大细胞（MC）通过分泌炎症介质促进肿瘤进展和免疫逃逸，在肿瘤微环境（TME）中发挥关键作用。在此，我们研究了使用药物重新利用组合——肼屈嗪（一种DNA甲基化抑制剂）和丙戊酸（一种组蛋白去乙酰化酶抑制剂（HDACi））进行表观遗传重编程对MC-癌细胞相互作用的影响。从一组肿瘤细胞系中选择了分泌干细胞因子（SCF）的人类癌细胞系（Ca Ski、MDA-MB-468和A549）。将HMC-I MC细胞系和选定的癌细胞系用肼屈嗪+丙戊酸（HV）处理72小时，通过台盼蓝排斥试验评估活力，结果显示所有细胞系的活力均持续降低。将HV处理的MCs的条件培养基（CM）应用于癌细胞，发现MDA-MB-468具有抗性。然后用HV处理的癌细胞的CM评估MC的迁移和趋化性，结果显示暴露于Ca Ski和MDA-MB-468上清液中的MCs迁移率降低，但暴露于A549上清液中的MCs迁移率未降低。流式细胞术分析表明，HV在表观遗传上抑制了促肿瘤细胞因子和MC趋化因子的表达，ITAC是唯一持续上调的细胞因子。这些发现表明，通过HV进行的药理学表观遗传重编程可调节MC驱动的肿瘤进展并重塑细胞因子网络，凸显了其作为癌症新型免疫表观遗传治疗策略的潜力。
