Antimetastatic effects of calycosin on osteosarcoma and the underlying mechanism

Abstract

Osteosarcoma (OS) refers to a malignant tumor with potential invasiveness and metastasis; however, the current chemotherapy of OS is lacking. Thus, the alternative drug for treating OS is urgent to explore. Calycosin (CC) is evidenced in our previous study to play the anti‐OS benefits for suppressing cancer cell proliferation. Consequently, further investigation of CC‐medicated anti‐invasive and metastatic effects against OS is needed. In the current study, the clinical samples of OS patients were collected for biological and staining assays, such as enzyme‐linked immunosorbent assay and polymerase chain reaction. Meanwhile, the cell line and tumor‐bearing nude mice were employed in assessing antimetastatic effects of CC against OS through biochemical tests and immunoassays. As a result, the OS patients exhibited upregulated neoplastic expressions of matrix metalloproteinase 2 (MMP2) and proliferating cell nuclear antigen (PCNA), cellular mRNAs and proteins of inhibitor of nuclear factor kappa‐B alpha (IκBα), and epithelial cell transforming sequence 2 (ECT2). In cell‐line study, CC‐treated human OS cells exhibited induced cell apoptosis, reduced cell proliferation, and cellular MMP2 and PCNA concentration, inhibited cell migration, lowered expressions of IκBα ECT2 mRNAs, and proteins. In tumor‐bearing nude mice study, CC‐treated mice resulted in the dose‐dependent reductions of tumor weights and intracellular MMP2 contents. As shown in further assays, neoplastic expressions of interleukin 6 protein, IκBα, ECT2 mRNAs, and proteins were downregulated dose‐dependently in CC‐treated tumor‐bearing mice. In conclusion, these investigative findings suggest that CC may play the potential anti‐invasive benefits against OS through suppressing metastasis‐associated IκBα/ECT2 molecular pathway.

Identification of key biomarkers and functional pathways in osteosarcomas with lung metastasis: Evidence from bioinformatics analysis

“…And the downregulation of ECT2 by siRNA and miR-223 could suppress osteosarcoma cell migration and invasion [58,59] . Moreover, Qiu et al [60] . found that Calycosin could inhibit osteosarcoma cell migration through restraining metastasis-associated IκBα/ECT2 signal pathway, but further research is needed to con rm the results.…”

Calycosin induces apoptosis via p38‑MAPK pathway‑mediated activation of the mitochondrial apoptotic pathway in human osteosarcoma 143B cells

“…Recent studies have extensively reported the anticancer and antimetastatic activities of calycosin in various types of cancer, including breast cancer, colorectal cancer, ovarian cancer and nasopharyngeal carcinoma ( 10 , 11 , 15 ). It was also reported that calycosin exerted an inhibitory effect on the growth of osteosarcoma ( 9 ). Sun et al ( 12 ) observed that calycosin induced apoptosis of estrogen receptor + MG-63 osteosarcoma cells via the PI3K/Akt/mTOR pathway.…”

“…Mitochondrial dependence signaling occurs through cleavage of caspase-9, which then activates downstream caspase-3, leading to cleavage of key cell substrates, including PARP, thereby inducing apoptosis ( 22 ). It was previously reported that calycosin exerts an anti-osteosarcoma effect, and its mechanism was associated with the activation of apoptosis ( 9 ). The present study also demonstrated that treatment with calycosin led to the cleavage of caspase-3, caspase-9 and PARP in osteosarcoma 143B cells.…”

“…Previous evidence has revealed that calycosin, a bioactive phytoestrogen isoflavone that is extracted from Trifolium pratense (red clover), possesses anti-allergic ( 5 ), anti-inflammatory ( 6 ), antifibrotic ( 7 ), anti-myocardial injury ( 8 ) and antitumor ( 9 – 11 ) properties. Calycosin may exert a potential antimetastatic effect on several types of cancer, including breast cancer, colorectal cancer, ovarian cancer and nasopharyngeal carcinoma ( 9 , 10 ). It also promotes apoptosis and autophagy in adenocarcinoma cells via sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK)-induced inhibition of the Akt/mammalian target of rapamycin (mTOR) pathway ( 11 ).…”

Enoxacin inhibits proliferation and invasion of human osteosarcoma cells and reduces bone tumour volume in a murine xenograft model

“…The degradation of ECM by MMPs is a key step in the invasion and metastasis processes in human cancers, and increased secretion and activity of MMPs are implicated in numerous types of malignant tumours ( 22 , 23 ). MMP2 and MMP9 are important members of the MMP family and inhibition of their expression is a strategy for reducing the invasion and metastasis of osteosarcoma ( 24 , 25 ). The current western blot analysis showed that enoxacin treatment downregulated the expression of MMP2 and MMP9 in 143B cells, which could be an effective way to inhibit osteosarcoma metastasis.…”