Cheng Zhongqiang, Huang Lixian, Zhang Yanshu, Yue Kaiyue, Jia Shunmo, Fang Zhijie, Lin Zhiqiang
Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233001, Anhui Province, China.
Department of Otorhinolaryngology, Yancheng No 1 People's Hospital Affiliated Hospital of Medical School, Nanjing University, The First people's Hospital of Yancheng, Yancheng, 224001, Jiangsu Province, China.
Cancer Cell Int. 2025 Aug 11;25(1):302. doi: 10.1186/s12935-025-03908-6.
Nasopharyngeal carcinoma (NPC) is a malignancy with high a mortality rate. This study investigates the impact of heme oxygenase-1 (HO-1) in cisplatin (CDDP) resistance in NPC.
The time-dependent effect of CDDP on two NPC cell lines (HK1 and C666-1) were investigated. CDDP-resistant cells were established by exposing the parental cells to increasing concentrations of CDDP. Parental cells received treatment of the HO-1 inducer Hemin while resistant cells received treatment of the HO-1 inhibitor ZnPP to explore the influence of HO-1 activity on CDDP resistance in NPC cell lines. Erastin was used to verify the effect of ferroptosis on CDDP sensitivity in cells. Parallel settings were performed in mouse xenograft tumor models for in vivo validation.
CDDP time-dependently reduced growth and mobility of NPC cells within the initial 48 h, but the cytotoxicity was no longer significantly enhanced afterward. HO-1 was upregulated in cells after CDDP treatment, showing correlation with acquired CDDP resistance. Inducing HO-1 activity in parental cells protected cells from oxidative damage, apoptosis, and ferroptosis, while suppressing HO-1 activity using ZnPP restored the therapeutic efficacy of CDDP in drug resistant cells. Moreover, the Erastin treatment also restored the cytotoxicity of CDDP to the resistant cells. In mice bearing xenograft tumors, treatment with either ZnPP or Erastin weakened the growth and weight of tumors.
This work suggests that HO-1 is pertinent to acquired CDDP resistance in NPC cells by suppressing oxidative stress and ferroptosis.
鼻咽癌（NPC）是一种死亡率很高的恶性肿瘤。本研究调查了血红素加氧酶-1（HO-1）对鼻咽癌顺铂（CDDP）耐药性的影响。
研究了CDDP对两种鼻咽癌细胞系（HK1和C666-1）的时间依赖性作用。通过将亲代细胞暴露于浓度递增的CDDP中来建立CDDP耐药细胞。亲代细胞接受HO-1诱导剂血红素处理，而耐药细胞接受HO-1抑制剂锌原卟啉处理，以探讨HO-1活性对鼻咽癌细胞系中CDDP耐药性的影响。使用艾拉司丁验证铁死亡对细胞中CDDP敏感性的影响。在小鼠异种移植肿瘤模型中进行平行设置以进行体内验证。
在最初的48小时内，CDDP时间依赖性地降低了鼻咽癌细胞的生长和迁移能力，但此后细胞毒性不再显著增强。CDDP处理后细胞中HO-1上调，显示与获得性CDDP耐药相关。在亲代细胞中诱导HO-1活性可保护细胞免受氧化损伤、凋亡和铁死亡，而使用锌原卟啉抑制HO-1活性可恢复CDDP在耐药细胞中的治疗效果。此外，艾拉司丁处理也恢复了CDDP对耐药细胞的细胞毒性。在携带异种移植肿瘤的小鼠中，锌原卟啉或艾拉司丁处理均减弱了肿瘤的生长和重量。
这项工作表明，HO-1通过抑制氧化应激和铁死亡与鼻咽癌细胞获得性CDDP耐药相关。
