Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The histone deacetylase inhibitor depsipeptide [(1S,4S,7Z,10S, 16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19, 22-pentone] (FK228) has attracted a great deal of interest because of its antiproliferative and apoptotic properties in various malignancies. Histone deacetylase inhibitors induce the expression of the multidrug resistance transporter P-glycoprotein (P-gp), and FK228 is a known P-gp substrate. Thus, FK228 seems to induce its own mechanism of drug resistance by up-regulating P-gp. The goal of this study was to establish human FK228-resistant osteosarcoma cell lines and to investigate whether there are mechanisms of FK228 resistance in addition to P-gp up-regulation. After 72 h in culture, the 50% inhibitory concentrations (IC(50)) of FK228 were 4.8 and 991 nM in HOS and HOS/FK8 cells, respectively, and 3.6 and 1420 nM in U2OS and U2OS/FK11 cells, respectively. Increased histone H3 acetylation was observed in FK228-resistant cell lines after a 1-h treatment with 10 nM FK228. Unlike in parental cells, significant P-gp overexpression was detected in FK228-resistant cells, and 10 nM FK228 treatment activated the mitogen-activated protein kinase (MAPK) pathway but did not induce Fas ligand (FasL) up-regulation or c-FLIP down-regulation. However, treatment of FK228-resistant cells with a combination of FK228 and mitogen-activated protein kinase kinase (MEK) inhibitors induced apoptosis, up-regulated FasL, and down-regulated c-FLIP. The expression and function of P-gp were unaltered by treatment with MEK inhibitors. These results indicate that the FK228 resistance of osteosarcoma cells is related to P-gp overexpression and MAPK pathway activation by FK228. MEK or P-gp inhibitors may be useful in overcoming this resistance.
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PMID:Involvement of extracellular signal-regulated kinase activation in human osteosarcoma cell resistance to the histone deacetylase inhibitor FK228 [(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone]. 1907 9

Emerging evidence shows that cytokines such as interleukins (ILs) are involved in the progression and chemoresistance of multiple tumors, including osteosarcoma (OS). Our present study established the doxorubicin (Dox) resistant human OS MG-63 and HOS cells and named them MG-63/Dox and HOS/Dox, respectively. The expression of IL-8, while not VEGFA, IL-32, or IL-34, was significantly increased in OS/Dox cells as compared with that in the parental cells. IL-8 neutralization antibody can significantly increase the Dox sensitivity of OS/Dox cells. Further, IL-8 can up regulate ABCB1, which encodes one important ATP-binding cassette (ABC) transporter /P-glycoprotein (P-gp). Mechanically, IL-8 increased the transcription of ABCB1 via up regulating its promoter activity, while had no effect on its protein or mRNA stability. Targeted inhibition of p65 can attenuate IL-8 induced transcription of ABCB1 in OS cells. Treatment OS cells with 5-aza-dC, the inhibitor of DNMT, had no effect on expression of IL-8. Expression of HDAC6 in MG-63/Dox and HOS/Dox cells was significantly greater than that in their parental cells. Knockdown of HDAC6 can suppress the expression of IL-8 in OS cells. Collectively, our data showed that HDAC6 mediated upregulation of IL-8 can regulate the Dox sensitivity of OS cells via transcriptionally regulating the expression of ABCB1. Targeted inhibition of IL-8 might be a potent potential approach for overcome the Dox resistance of OS cells and helpful for clinical therapy of OS patients.
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PMID:Histone deacetylase 6 regulated expression of IL-8 is involved in the doxorubicin (Dox) resistance of osteosarcoma cells via modulating ABCB1 transcription. 3027 44