title: Targeting HDAC with a novel inhibitor effectively reverses paclitaxel resistance in non-small cell lung cancer via multiple mechanisms.
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-resistant NSCLC and provide a promising therapeutic strategy to overcome paclitaxel-acquired resistance.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Zou
authors.affiliation: Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Wu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D006655:Histone Deacetylases; D017239:Paclitaxel