Fan Hsiu-Lung, Liu Shu-Ting, Chang Yung-Lung, Chiu Yi-Lin, Huang Shih-Ming, Chen Teng-Wei
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Front Oncol. 2022 May 23;12:843742. doi: 10.3389/fonc.2022.843742. eCollection 2022.
Hepatocellular carcinoma (HCC) is the primary histological subtype of liver cancer, and its incidence rates increase with age. Recently, systemic therapies, such as immune checkpoint inhibitors, monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been more beneficial than conventional therapies for treating HCC. Nonetheless, the prognosis of late-stage HCC remains dismal because of its high recurrence rates, even with substantial advances in current therapeutic strategies. A new treatment, such as a combination of current systemic therapies, is urgently required. Therefore, we adopted a repurposing strategy and tried to combine ascorbate with TKIs, including lenvatinib and regorafenib, in HepG2 and Hep3B cells. We investigated the potential functional impact of pharmacological concentrations of ascorbate on the cell-cycle profiles, mitochondrial membrane potential, oxidative response, synergistic effects of lenvatinib or regorafenib, and differential responsiveness between HepG2 and Hep3B cells. Our data suggest that the relative level of cell density is an important determinant for ascorbate cytotoxicity in HCC. Furthermore, the data also revealed that the cytotoxic effect of pharmacological concentrations of ascorbate might not be mediated our proposed elevation of ROS generation. Ascorbate might be involved in redox homeostasis to enhance the efficacy of TKIs in HepG2 and Hep3B cells. The synergistic effects of ascorbate with TKIs (lenvatinib and regorafenib) support their potential as an adjuvant for HCC targeted TKI therapy. This research provides a cheap and new combinatory therapy for HCC treatment.
肝细胞癌（HCC）是肝癌的主要组织学亚型，其发病率随年龄增长而增加。最近，免疫检查点抑制剂、单克隆抗体和酪氨酸激酶抑制剂（TKIs）等全身治疗方法在治疗HCC方面比传统疗法更具优势。尽管如此，晚期HCC的预后仍然很差，因为即使目前的治疗策略取得了重大进展，其复发率仍然很高。迫切需要一种新的治疗方法，例如将目前的全身治疗方法联合使用。因此，我们采用了一种重新利用药物的策略，试图在HepG2和Hep3B细胞中将抗坏血酸与包括乐伐替尼和瑞戈非尼在内的TKIs联合使用。我们研究了药理浓度的抗坏血酸对细胞周期分布、线粒体膜电位、氧化反应、乐伐替尼或瑞戈非尼的协同作用以及HepG2和Hep3B细胞之间的差异反应性的潜在功能影响。我们的数据表明，细胞密度的相对水平是抗坏血酸对HCC细胞毒性的一个重要决定因素。此外，数据还显示，药理浓度的抗坏血酸的细胞毒性作用可能不是由我们提出的活性氧生成增加介导的。抗坏血酸可能参与氧化还原稳态，以增强TKIs在HepG2和Hep3B细胞中的疗效。抗坏血酸与TKIs（乐伐替尼和瑞戈非尼）的协同作用支持了它们作为HCC靶向TKI治疗辅助药物的潜力。这项研究为HCC治疗提供了一种廉价的新联合疗法。
