Institute of Reproductive & Stem Cell Engineering, Central South University, Changsha 410083, China.
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Int J Mol Sci. 2019 Sep 5;20(18):4360. doi: 10.3390/ijms20184360.
The prognosis for non-resectable or recurrent osteosarcoma (OS) remains poor. The finding that the majority of OS overexpress the protooncogene HER2 raises the possibility of using HER2 as a therapeutic target. However, clinical trials on the anti-HER2 antibody trastuzumab (TRA) in treating OS find no therapeutic benefit. HER2 overexpression in OS is not generally associated with gene amplification, with low-level expression regarded as HER2 "negative", as per criteria used to classify breast cancer HER2 status. Nevertheless, active HER2-targeting approaches, such as virus-based HER2 vaccines or CAR-T cells have generated promising results. More recently, it has been found that the noncovalent association of TRA with nanomaterial graphene oxide (GO) generates stable TRA/GO complexes capable of rapidly killing OS cells. TRA/GO induces oxidative stress and strong HER2 signaling to elicit immediate degradation of both cIAP (cellular inhibitor of apoptosis protein) and caspase 8, leading to activation of necroptosis. This is an attractive mechanism of cancer cell death as chemo/apoptosis-resistant tumors may remain susceptible to necroptosis. In addition, necroptosis is potentially immunogenic to promote tumor immunity, as opposed to apoptosis that tends to silence tumor immunity. Currently, no established anticancer therapeutics are known to eliminate cancers by necroptosis. The aim of this article is to review the rationale and mechanisms of TRA/GO-mediated cytotoxicity.
不可切除或复发性骨肉瘤（OS）的预后仍然较差。大多数 OS 过度表达原癌基因 HER2 的发现提出了将 HER2 用作治疗靶点的可能性。然而，针对抗 HER2 抗体曲妥珠单抗（TRA）治疗 OS 的临床试验并未发现治疗益处。OS 中 HER2 的过表达通常与基因扩增无关，根据用于分类乳腺癌 HER2 状态的标准，低水平表达被视为 HER2“阴性”。然而，积极的 HER2 靶向方法，如基于病毒的 HER2 疫苗或 CAR-T 细胞，已经产生了有希望的结果。最近，人们发现 TRA 与纳米材料氧化石墨烯（GO）的非共价结合生成了能够快速杀死 OS 细胞的稳定 TRA/GO 复合物。TRA/GO 诱导氧化应激和强烈的 HER2 信号传导，导致细胞凋亡抑制剂（cIAP）和半胱天冬酶 8 的迅速降解，从而激活坏死性凋亡。这是一种有吸引力的癌细胞死亡机制，因为化疗/凋亡耐药肿瘤可能仍然容易发生坏死性凋亡。此外，坏死性凋亡具有潜在的免疫原性，可以促进肿瘤免疫，而凋亡往往会使肿瘤免疫沉默。目前，尚无已知的抗癌治疗方法可通过坏死性凋亡消除癌症。本文的目的是综述 TRA/GO 介导的细胞毒性的原理和机制。
