Together, these experiments provide preclinical evidence that the FDA-approved DNA methylation inhibitor DAC may be repurposed to treat patients with osteosarcoma based on its efficacy to decrease proliferation, to induce osteoblast differentiation, and to reduce metastasis to visceral organs.<b>Significance:</b> These findings describe the effects of DNA methyltransferase inhibition on ERα and its potential role as a tumor suppressor in osteosarcoma.<i>See related commentary by Roberts, p. 1034</i><i>See related article by El Ayachi and colleagues; Cancer Res 79(5);982-93</i>.
To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system.
As a result, the miRNA-TF-mRNA regulatory network, including 1049 nodes (516 miRNA, 25 TFs, and 508 DEGs) and 15942 edges (interaction relationships, such as Pparg-Abca1 and miR-590-3p-AXIN2), was constructed, from which three significant modules were extracted and modules 2 and 3 contained interactions between miRNAs/TFs and DEGs such as miR-103-3p-<i>AXIN2</i>, miR-124-3p-<i>AR</i>-<i>Tgfb1i1</i>, and miR-27a-3p-<i>PPARG</i>-<i>Abca1</i>. miR-27a-3p was a known miRNA associated with OS.
Moreover, we assessed the expression of P-gp after suppressing ASS1 in Dox-sensitive cells (MCF-7 and KHOS) and after transfecting ASS1 into Dox-resistant cells (ES-X, VAESBJ, ASPS-KY and KHOSR2).
In the osteosarcoma cell lines, etoposide and doxorubicin were better inducers of P450 3A4 and MDR1 than rifampin. siRNA against PXR down-regulated P450 3A4 expression only in the osteosarcoma cell line.
These findings indicate that P-glycoprotein overexpression is causally associated with a low malignant potential of osteosarcoma cells, and open new insights on the role and functions of P-glycoprotein activity.
The overexpression of the ezrin deletion mutant entirely restored drug susceptibility of osteosarcoma cells, consistent with Pgp dislocation to cytoplasmic compartments and abrogation of G(M1) /Pgp co-localization at the plasma membrane.
Here, based on our previous study, we further identified that the lncRNA FOXC2-AS1 and its antisense transcript FOXC2 are positively up-regulated in doxorubicin-resistant osteosarcoma cell lines and tissues, correlate with poor prognosis and promote doxorubicin resistance in osteosarcoma cells in vitro and in vivo.
In conclusion, icariin possesses a reversal effect on multidrug resistance in MG-63/DOX cells through down-regulation of the MDR1 and the PI3K/Akt pathway, and has the potential to be an adjunct to chemotherapy for osteosarcoma.
Thus, we concluded that lncRNA ODRUL may act as a pro-doxorubicin-resistant molecule through inducing the expression of the classical multidrug resistance-related ABCB1 gene in osteosarcoma cells .These findings may provide a novel target for reversing doxorubicin resistance in OS.
Here, we demonstrated that FK228 and apicidin exhibited strong resistance in doxorubicin-resistant clones of OS and EFTs expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) and that P-gp and MRP1 might play a crucial role in the resistance mechanism to FK228 and apicidin.
Resistance to several cytotoxic agents (MultiDrug Resistance MDR), including anthracyclines, vinca alkaloids and epipodophylline derivatives can occur in human osteosarcoma (OS) cells, detected by the overexpression of a 170 kD glycoprotein (p170), as a result of increased expression of the MDR gene (mdr1).