Anti-HDAC6 monoclonal antibody, clone FQS2709(3 Knockout Validated

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.

Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected against rhabdomyolysis-induced AKI with good safety. However, whether 23BB possessed favorable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by acute kidney dysfunction and pathological changes, companied by the overexpression of HDAC6 in tubular epithelial cells. Pharmacological inhibition of HDAC6 by the treatment of 23BB significantly attenuated sCr, BUN and renal tubular damage. Mechanistically, 23BB enhanced the acetylation of histone H3 to reduce the HDAC6 activity. Cisplatin-induced AKI triggered multiple signal mediators of endoplasmic reticulum (ER) stress including PERK, ATF6 and IRE1 pathway, as well as CHOP, GRP78, p-JNK and caspase 12 proteins. Oral administration of our HDAC6i 23BB at a dose of 40 mg/kg/d for 3 days notably improved above-mentioned responses in the injured kidney tissues. HDAC6 inhibition also reduced the number of TUNEL-positive tubular cells and regulated apoptosis-related protein expression. Overall, these data highlighted that HDAC6 inhibitor 23BB modulated apoptosis via the inhibition of ER stress in the tubular epithelial cells of cisplatin-induced AKI.