Chitsike Lennox, Bertucci Antonella, Vazquez Marcelo, Lee Steve, Unternaehrer Juli J, Duerksen-Hughes Penelope J
Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, United States.
Department of Radiation Medicine, Loma Linda University School of Medicine, Loma Linda, CA, United States.
Front Oncol. 2023 Feb 10;13:1070485. doi: 10.3389/fonc.2023.1070485. eCollection 2023.
Treatment-related toxicity following either chemo- or radiotherapy can create significant clinical challenges for HNSCC cancer patients, particularly those with HPV-associated oropharyngeal squamous cell carcinoma. Identifying and characterizing targeted therapy agents that enhance the efficacy of radiation is a reasonable approach for developing de-escalated radiation regimens that result in less radiation-induced sequelae. We evaluated the ability of our recently discovered, novel HPV E6 inhibitor (GA-OH) to radio-sensitize HPV+ and HPV- HNSCC cell lines to photon and proton radiation.
Radiosensitivity to either photon or proton beams was assessed using various assays such as colony formation assay, DNA damage markers, cell cycle and apoptosis, western blotting, and primary cells. Calculations for radiosensitivity indices and relative biological effectiveness (RBE) were based on the linear quadratic model.
Our results showed that radiation derived from both X-ray photons and protons is effective in inhibiting colony formation in HNSCC cells, and that GA-OH potentiated radiosensitivity of the cells. This effect was stronger in HPV+ cells as compared to their HPV- counterparts. We also found that GA-OH was more effective than cetuximab but less effective than cisplatin (CDDP) in enhancing radiosensitivity of HSNCC cells. Further tests indicated that the effects of GA-OH on the response to radiation may be mediated through cell cycle arrest, particularly in HPV+ cell lines. Importantly, the results also showed that GA-OH increases the apoptotic induction of radiation as measured by several apoptotic markers, even though radiation alone had little effect on apoptosis.
The enhanced combinatorial cytotoxicity found in this study indicates the strong potential of E6 inhibition as a strategy to sensitize cells to radiation. Future research is warranted to further characterize the interaction of GA-OH derivatives and other E6-specific inhibitors with radiation, as well as its potential to improve the safety and effectiveness of radiation treatment for patients with oropharyngeal cancer.
化学疗法或放射疗法后的治疗相关毒性会给头颈部鳞状细胞癌（HNSCC）患者带来重大临床挑战，尤其是那些患有与人乳头瘤病毒（HPV）相关的口咽鳞状细胞癌的患者。识别并表征可增强放射疗效的靶向治疗药物，是制定能减少放射诱导后遗症的降阶梯放射治疗方案的合理方法。我们评估了我们最近发现的新型HPV E6抑制剂（GA-OH）使HPV阳性和HPV阴性HNSCC细胞系对光子和质子辐射产生放射增敏作用的能力。
使用多种检测方法评估对光子束或质子束的放射敏感性，如集落形成试验、DNA损伤标志物、细胞周期和凋亡、蛋白质免疫印迹法以及原代细胞检测。放射敏感性指数和相对生物效应（RBE）的计算基于线性二次模型。
我们的结果表明，来自X射线光子和质子的辐射均能有效抑制HNSCC细胞中的集落形成，并且GA-OH增强了细胞的放射敏感性。与HPV阴性细胞相比，这种作用在HPV阳性细胞中更强。我们还发现，在增强HSNCC细胞的放射敏感性方面，GA-OH比西妥昔单抗更有效，但比顺铂（CDDP）效果差。进一步的检测表明，GA-OH对放射反应的影响可能是通过细胞周期阻滞介导的，尤其是在HPV阳性细胞系中。重要的是，结果还表明，尽管单独的辐射对凋亡几乎没有影响，但通过几种凋亡标志物测量，GA-OH可增加辐射诱导的凋亡。
本研究中发现的增强的联合细胞毒性表明，抑制E6作为使细胞对辐射敏感的策略具有强大潜力。有必要进行进一步研究，以进一步表征GA-OH衍生物和其他E6特异性抑制剂与辐射的相互作用，以及其改善口咽癌患者放射治疗安全性和有效性的潜力。
