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

L, Wang; Li, H; Ren, Yong; Zou, Shenglan; Fang, Wu-hong; Jiang, Xiaorui; Jia, Lei; Li, M; Liu, X; Yuan, Xiangzhong; Chen, G; Yang, Jinyu; Wu, Chunfu

doi:10.1038/cddis.2015.328

Cited by 72 publications

(76 citation statements)

References 35 publications

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“…In fact, a very recent study showed that treatment of paclitaxel-resistant lung cancer cell line with a novel HDACi sensitized the cells to paclitaxel-induced cytotoxicity both in vitro and in vivo. 58 Synergy between taxanes and HDACi in inducing cytotoxicity has been previously demonstrated in vitro and in xenograft tumor models of ovarian, breast, and prostate cancer. 30,[59][60][61][62][63][64][65][66][67][68] Belinostat has been found to be synergistic with taxanes in inducing apoptosis in prostate and ovarian cell lines and in clinical samples from ovarian tumors grown in organoid culture.…”

Section: Discussionmentioning

confidence: 94%

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, celltype specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

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Section: Discussionmentioning

confidence: 94%

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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“…HDAC inhibitors are reported to enhance the anti-tumor activities of other chemotherapeutic agents [5,6]. Various clinical trials of combination therapies of HDAC inhibitors have been carried out.…”

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Ono

Sowa

Horinaka

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC. Methods We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses. Results The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone. Conclusion We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.

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“…A549-CHI-R cells, which exhibit enhanced HDAC activity, demonstrated cross-resistance to GEM, TAX and VNR in the present study. Consistent with this, paclitaxel-resistant NSCLC cells exhibited enhanced HDAC activity and tumorigenicity (36). Increased HDAC1 expression in NSCLC tissue predicted a poor prognosis for patients treated with paclitaxel (36).…”

Section: Discussionmentioning

confidence: 67%

“…Consistent with this, paclitaxel-resistant NSCLC cells exhibited enhanced HDAC activity and tumorigenicity (36). Increased HDAC1 expression in NSCLC tissue predicted a poor prognosis for patients treated with paclitaxel (36). TAX and VNR are microtubule-targeting drugs; their most potent cytotoxic action is the suppression of microtubule dynamics, leading to mitotic arrest and subsequent cell death (37).…”

Section: Discussionmentioning

confidence: 89%

Molecular, biological characterization and drug sensitivity of chidamide‑resistant non‑small cell lung cancer cells

Luo

Zhu

et al. 2017

Oncol Lett

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Abstract. Chidamide, a histone deacetylase (HDAC) inhibitor, has been applied in clinical trials for various types of hematological and solid tumors. Although acquired resistance is common in chemotherapy, the mechanism of resistance to chidamide is poorly characterized. The goal of the present study was to explore, in detail, the mechanism for the induced resistance to chidamide, and investigate a potential cross-resistance to other chemotherapeutic drugs. A549 cells were exposed to gradually increasing chidamide concentrations to establish a chidamide-resistant non-small cell lung cancer cell line (A549-CHI-R). The IC 50 for chidamide, the proliferation inhibition rate, the total HDAC activity and the HDAC protein level were determined by an MTT assay, colony formation, a fluorometric HDAC activity assay and western blotting, respectively. Overexpression of the HDAC1 gene and HDAC1 gene-knockdown were achieved via plasmid transfection. A549-CHI-R cells demonstrated increased resistance to chidamide (8.6-fold). HDAC1 protein degradation was inhibited and HDAC activity was significantly higher in the A549-CHI-R cells relative to the parental A549 cells. A549-CHI-R cells demonstrated cross-resistance to paclitaxel, vinorelbine and gemcitabine, but not to cisplatin (CDDP) or 5-fluorouracil (5-FU). These results indicated that HDAC1 may be associated with resistance to chidamide, and HDAC1 may therefore be a predictive marker for chidamide sensitivity in cancer. In addition, A549-CHI-R cells remained sensitive to 5-FU and CDDP, indicating a potential strategy for cancer therapy.

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

Cited by 72 publications

References 35 publications

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

Molecular, biological characterization and drug sensitivity of chidamide‑resistant non‑small cell lung cancer cells

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