The Thioredoxin Reductase Inhibitor Auranofin Suppresses Pulmonary Metastasis of Osteosarcoma, But Not Local Progression

Abstract

Background/Aim: Auranofin (AUR), a thioredoxin reductase (TXNRD) inhibitor, shows anticancer activity against several cancers. This study investigated the effects of AUR on the local progression and pulmonary metastasis of osteosarcoma (OS). Materials and Methods: Publicly available expression cohorts were analysed to study the relationship between TXNRD-2 expression and the survival of patients with OS. The murine OS cell line LM8 was stimulated with AUR. Cell viability, apoptosis-related protein levels, caspase activity, and wound healing were analysed. Tumor progression and pulmonary metastasis were investigated in C3H mice implanted with LM8 cells. Results: High-level expression of TXNRD-2 represented a negative prognostic factor for metastasis and overall survival in patients with OS. AUR induced apoptosis of OS cells via the oxidative stress-MAPK-Caspase 3 pathway, and suppressed the migration of OS cells. AUR inhibited the pulmonary metastasis of OS, but not local progression. Conclusion: AUR represents a potential therapeutic drug for suppressing pulmonary metastasis of OS.Osteosarcoma (OS) is a relatively rare malignant tumor with a high incidence in the adolescent and young adult population, and is associated with poor survival. Treatment of OS includes surgery and perioperative chemotherapies (1). Standard chemotherapy for pediatric patients involves the use of doxorubicin, cisplatin, and high-dose methotrexate. However, the five-year survival probability for OS is poor, and it is worse for patients with pulmonary metastases. Chemotherapies used at present include conventional cytotoxic agents with strong side effects; therefore, the development of novel therapeutic agents is desirable. The oxidation-reduction (redox) system is an essential regulator of various metabolic functions of the cell. Thioredoxin (TXN), a key molecule in the redox system, plays an active role in scavenging reactive oxygen species (ROS), which are associated with the development of several diseases, including cancers and sarcomas (2, 3). ROS has been shown to activate mitogen-activated protein kinases (MAPKs), such as p38 and c-Jun N-terminal kinase (JNK), and induce apoptosis in cancer cells (4). TXN reductases (TXNRDs) are enzymes that catalyse the reduction of TXN and regulate TXN activity. Members of the TXNRD family comprise three isoforms including cytosolic TXNRD-1, mitochondrial TXNRD-2, and TXNRD-3. TXNRD-2 has been reported to be often overexpressed in cancer cells thereby conferring resistance to apoptosis (5); TXNRDs represent therapeutic targets of several cancers (6). Auranofin (AUR) is an anti-rheumatic drug approved by the US Food and Drug Administration (FDA) that functions as a TXNRD inhibitor and has anticancer properties against several cancers (7, 8). The effect of AUR alone on local progression and pulmonary metastases of OS has not been reported in previous studies. Therefore, we investigated the effects of AUR on local progression and pulmonary metastasis of OS in vitro and in vivo. Materials and Methods...

ELF3 Is a Target That Promotes Therapeutic Efficiency in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer Cells via Inhibiting PKCί

“…Although ANF treatment (3.0 µM in A549 cells, 1.0 µM in H1975 cells) slightly increased cleaved PARP levels, the combination treatment induced the levels of cleaved PARP further. ANF treatment has been reported to increase the level of cleaved Caspase-3, which cleaves PARP, in murine osteosarcoma cells [23]. As cleaved PARP is a marker of apoptosis, these results suggest that the combination of ANF/GEF induces apoptosis of cells, and these results are consistent with the apoptotic analysis data (Figure 5C,D).…”

The Relationship between PBLS and Osteosarcoma Distribution in Different Subgroups and the Survival and Prognosis of Osteosarcoma

“…Te early symptoms are mostly pain and swelling at the lesion site. Due to the atypical symptoms, patients cannot be concerned, and most patients have early metastases when they visit a doctor, so the treatment of OS is difcult [8]. Immunotherapy has historically been one of the most widely used strategies to treat many types of cancers, and therapies associated with T cell responses, such as immune checkpoint inhibitors and chimeric antigen receptor T cell therapy, have been considered good options for certain cancers.…”

“…Te PBLS count refects the changes of some lymphocyte subsets and has been widely used in malignant solid tumors, which is a comprehensive, simple, and dynamic immune evaluation index. Moreover, it has been demonstrated that PBLS mediate the apoptosis of liver cancer cells, and the ratio of PBLS to neutrophils or monocytes is of great value in evaluating the prognosis of liver cancer patients [8]. However, there are only a few studies on PBLS for evaluating the prognosis of OS.…”

Thioredoxin Reductase Inhibitor Suppresses the Local Progression of Rhabdomyosarcoma With PDX Models

“…The mice were divided into groups of five animals with similar distributions of tumor sizes. They were treated with either 200 μl vehicle control (40% PEG 300+60% sterile PBS) or 10 mg kg −1 AUR intraperitoneally, every day until the end of the study, as described in previous literature (8). Tumor measurements and animal weights were monitored weekly in a non-blinded manner.…”

“…Thioredoxin (TRX) and TRX reductases (TXNRD), the key molecules of the redox system, function as scavengers of reactive oxygen species (ROS) and are associated with the development of several diseases, including cancer (6). A recent report highlighted that the TRX inhibitor PX-12 and the TXNRD inhibitor auranofin (AUR) were highly effective in inhibiting the local progression and pulmonary metastasis of osteosarcoma (OS) in vivo (7,8). This indicates that the redox system, which includes TRX and TXNRD, may be a valuable target for OS treatment.…”