Histone Deacetylase Inhibitor Trichostatin A Enhances Antitumor Effects of Docetaxel or Erlotinib in A549 Cell Line

Zhang, Quncheng; Jiang, Shujuan; Zhang, Song; Ma, Xiaolong

doi:10.7314/apjcp.2012.13.7.3471

Cited by 29 publications

(16 citation statements)

References 25 publications

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“…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. 65,67 Although most of these studies did not explore mechanism, cytotoxicity induced by vorinostat and paclitaxel in breast cancer cell lines was accompanied by increased induction of G2/M arrest.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…29 Briefly, A2780 cells were seeded in 6-well plates (~5,000 cells/well) and cultured overnight before treatment with DTX, XNMs, DTX/LNMs, and DTX/XNMs, respectively. The drug concentration in each sample was kept at 6 nM.…”

Section: Immunofluorescence Analysismentioning

confidence: 99%

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

Xiao¹,

Wang²

2015

IJN

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To study the effects of X-shaped amphiphilic block copolymers on delivery of docetaxel (DTX) and the reduction-sensitive property on drug release, a novel reduction-sensitive amphiphilic copolymer, (PLGA) 2 -SS-4-arm-PEG 2000 with a Gemini-like X-shape, was successfully synthesized. The formation of nanomicelles was proved with respect to the blue shift of the emission fluorescence as well as the fluorescent intensity increase of coumarin 6-loaded particles. The X-shaped polymers exhibited a smaller critical micelle concentration value and possessed higher micellar stability in comparison with those of linear ones. The size of X-shaped (PLGA) 2 -SS-4-arm-PEG 2000 polymer nanomicelles (XNMs) was much smaller than that of nanomicelles prepared with linear polymers. The reduction sensitivity of polymers was confirmed by the increase of micellar sizes as well as the in vitro drug release profile of DTX-loaded XNMs (DTX/XNMs). Cytotoxicity assays in vitro revealed that the blank XNMs were nontoxic against A2780 cells up to a concentration of 50 µg/mL, displaying good biocompatibility. DTX/XNMs were more toxic against A2780 cells than other formulations in both dose- and time-dependent manners. Cellular uptake assay displayed a higher intracellular drug delivery efficiency of XNMs than that of nanomicelles prepared with linear polymers. Besides, the promotion of tubulin polymerization induced by DTX was visualized by immunofluorescence analysis, and the acceleration of apoptotic process against A2780 cells was also imaged using a fluorescent staining method. Therefore, this X-shaped reduction-sensitive (PLGA) 2 -SS-4-arm-PEG 2000 copolymer could effectively improve the micellar stability and significantly enhance the therapeutic efficacy of DTX by increasing the cellular uptake and selectively accelerating the drug release inside cancer cells.

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“…In the repression of gene transcription expression, histone deacetylases (HDACs) play a significant role by changing chromatin structure (Thiagalingam et al, 2003) and affecting proliferation, cell cycling, apoptosis, differentiation, DNA replication, DNA damage response and migration of cancer cells (Langer et al, 2010;Li et al, 2013a). It has been reported that over-expression of HDACs has been detected in lung cancer tissues (Sasaki et al, 2004;Krusche et al, 2005;Nakagawa et al, 2007;Fritzsche et al, 2008;Weichert et al, 2008a;Weichert et al, 2008b;Kallsen et al, 2012) and that the expression of HDAC promotes the progress of lung cancer (Zhang et al, 2012b). Specifically, the expression of HDAC1 is related to advanced non small cell lung cancers (NSCLCs) (Minamiya et al, 2011), and an independent predictor of poor prognosis in patients with NSCLC (Bremnes et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Matrine Reduces Proliferation of Human Lung Cancer Cells by Inducing Apoptosis and Changing miRNA Expression Profiles

Liu

Li²,

Qin³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Histone Deacetylase Inhibitor Trichostatin A Enhances Antitumor Effects of Docetaxel or Erlotinib in A549 Cell Line

Cited by 29 publications

References 25 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

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

Matrine Reduces Proliferation of Human Lung Cancer Cells by Inducing Apoptosis and Changing miRNA Expression Profiles

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