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.
Highlights
Paclitaxel resistance can be achieved through several mechanisms, including tubulin isoforms/mutations and the alteration of drug efflux pumps.[7,8] Other mechanisms of resistance have been identified, including deregulation of apoptotic signaling pathways and activation of hypoxiainduced factor 1 (HIF-1) signaling.[9,10,11] in spite of these advances, treatment of paclitaxel-resistant patients remains a critical clinical challenge
Our results indicated that histone deacetylases (HDACs) activity was increased to 1.5-fold in A549/paclitaxel resistance cells (A549/T) cells when compared with that of parental A549 cells
In consistence with the increasing HDAC activity, its substrates, including p21, acetylated Histone 3 (Ac-H3), and acetylated Histone 4 (Ac-H4), were changed in A549/T cells, suggesting that HDAC activity is increased in A549/T cells
Summary
Paclitaxel resistance can be achieved through several mechanisms, including tubulin isoforms/mutations and the alteration of drug efflux pumps.[7,8] Other mechanisms of resistance have been identified, including deregulation of apoptotic signaling pathways and activation of hypoxiainduced factor 1 (HIF-1) signaling.[9,10,11] in spite of these advances, treatment of paclitaxel-resistant patients remains a critical clinical challenge. HDAC inhibitors in combination with DNA-damaging agents, taxanes, targeted agents, death receptor agonists, and hormonal therapies.[18] HDAC inhibitors have been found to reverse cytotoxic and targeted agent resistance in various tumors.[18,19,20] whether HDACs are implicated in paclitaxel resistance in NSCLCs is still not elucidated. Patients owing higher HDAC1 with lower p21 expression tumors showed chemotherapy resistance and bad outcome while taking paclitaxel as a chemotherapy agent. We identified a novel HDACs inhibitor, SNOH-3, which was more potent than FDAapproved HDAC inhibitor SAHA to inhibit HDAC activity, induce cell apoptosis, and suppress cell migration, invasion and angiogenesis. When SNOH-3 combined with paclitaxel could overcome paclitaxel resistance through inhibiting HDAC activity, leading to the induction of apoptosis and suppression of angiogenesis. Our results identify a therapeutic strategy to abrogate acquired resistance to paclitaxel in NSCLC, and imply that HDAC1 along with p21 might be a predictive biomarker for paclitaxel treatment
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