Targeting HDAC with a novel inhibitor effectively reverses paclitaxel resistance in non-small cell lung cancer via multiple mechanisms

Cell Death & Disease
L WangC Wu

Abstract

Chemotherapy paclitaxel yields significant reductions in tumor burden in the majority of advanced non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits its clinical use. Here we demonstrated that the histone deacetylase (HDAC) was activated in paclitaxel-resistant NSCLC cells, and its activation promoted proliferation and tumorigenesis of paclitaxel-resistant NSCLC cells in vitro and in vivo. By contrast, knockdown of HDAC1, a primary isoform of HDAC, sensitized resistant cells to paclitaxel in vitro. Furthermore, we observed that overexpression of HDAC1 was associated with the downregulation of p21, a known HDAC target, in advanced NSCLC patients with paclitaxel treatment, and predicted chemotherapy resistance and bad outcome. In addition, we also identified a novel HDACs inhibitor, SNOH-3, which inhibited HDAC expression and activity, induced cell apoptosis, and suppressed cell migration, invasion and angiogenesis. Notably, co-treatment with SNOH-3 and paclitaxel overcome paclitaxel resistance through inhibiting HDAC activity, leading to the induction of apoptosis and suppression of angiogenesis in vitro and in preclinical model. In summary, our data demonstrate a role of HDAC in paclitaxel-resistan...Continue Reading

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Citations

Apr 6, 2017·Angiogenesis·Robert H BerndsenPatrycja Nowak-Sliwinska
Apr 27, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Yimin LuXudong Lu
May 8, 2018·Medicinal Research Reviews·Heba M HeshamKhaled A M Abouzid
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May 13, 2021·Cell Death & Disease·Sonali BahlEdward Seto
Jun 28, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Lingyue GaoLihui Wang

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Methods Mentioned

BETA
acetylation
histones acetylation
xenografts
protein assay
X-ray
FACS
xenograft

Software Mentioned

SPSS
ImageXpress R
Calcusyn
ImageXpress
SPSS11

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