Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies

Qian, Xiaozhong; LaRochelle, William J.; Ara, Gulshan; Wu, Frank; Petersen, Kamille Dumong; Thougaard, Annemette; Sehested, Maxwell; Lichenstein, Henri S.; Jeffers, Michael

doi:10.1158/1535-7163.mct-06-0111

Cited by 130 publications

(99 citation statements)

References 36 publications

(37 reference statements)

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“…It has been reported previously that hydroxamic acid-based inhibitors such as belinostat, are potent inducers of differentiation and/or apoptosis in transformed cells in culture including prostate cancer cells (10,28,29). Here we confirm that Belinostat, a member of hydroxamic acid-based inhibitors, suppresses, in vitro and in vivo, the growth of a wide panel of prostate tumor cells with graded androgen dependence at micromolar concentrations.…”

Section: Discussionsupporting

confidence: 87%

Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models

Gravina

Marampon²,

Giusti³

et al. 2011

Int J Oncol

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Abstract. Histone deacetylase inhibitors (HDACi) are promising epigenetic cancer chemotherapeutics rapidly approaching clinical use. In this study, we tested using in vitro and in vivo models the differential biological effects of a novel HDAC inhibitor [belinostat (PXD101)], in a wide panel of androgensensitive and androgen-independent tumor cells. Belinostat significantly increased acetylation of histones H3 and H4. Belinostat potently inhibited the growth of prostate cancer cell lines (IC 50 range from 0.5 to 2.5 µM) with cytotoxic activity preferentially against tumor cells. This agent induced G 2 /M arrest and increased significantly the percentage of apoptosis mainly in androgen-sensitive tumor cells confirming its growthinhibitory effects. The cell death mechanisms were studied in three different prostate cancer cell lines with different androgen dependence and expression of androgen receptor; LAPC-4 and 22rv1 (androgen-dependent and expressing androgen receptor) and PC3 (androgen-independent not expressing androgen receptor). Belinostat induced the expression of p21 and p27, acetylation of p53 and G 2 /M arrest associated with Bcl2 and Bcl-Xl downmodulation and significant reduction of survivin, IAPs and Akt/pAkt and increased caspase-8 and -9 expression/activity. Belinostat effectiveness was dependent on the androgen receptor (AR), since the stable transfection of AR greatly increased the efficacy of this HDAC inhibitor. These observations were correlated using in vivo models. We demonstrated that belinostat preferentially resulted in antitumor effect in androgen-dependent tumor cells expressing AR. Our findings provide evidence that belinostat may be a promising anticancer drug for prostate cancer expressing AR, supporting its clinical role in prostate cancer.

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Section: Discussionsupporting

confidence: 87%

Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models

Gravina

Marampon²,

Giusti³

et al. 2011

Int J Oncol

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“…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. 62 A study of Hela cells showed that combining the hydroxamate HDACi, trichostatin A, with paclitaxel disrupted the association of BubR1 with kinetochores and reduced clonogenic survival.…”

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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“…These results are summarised in table 3. The exposure following oral dosing of belinostat was variable but sufficient to achieve histone acetylation ( Figure 2) and in a potentially therapeutic range based on observations in pre-clinical models [8][9][10]. Total mean daily AUC of 2767 1453 ng hr/ml (8.7 4.6 M hr) resulted from a dose of 1000 mg/m 2 once daily (qd).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Steele

Plumb

Vidal

et al. 2010

Cancer Chemother Pharmacol

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PurposeThe primary objective of this sub-study, undertaken as an extension to the previously reported phase I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary PD studies were also performed to enable comparison of the biologic effects of the oral and intravenous formulations. Patients and MethodsOral belinostat was administered in a range of doses and schedules (once, twice, or thrice daily), on either day 1 or days 1 -5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase I trial of intravenous belinostat.Serial blood samples were collected for pharmacokinetic and pharmacodynamic (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. ResultsA total mean daily AUC of 2767 1453 ng hr/ml (8.7 4.6 M hr) resulted from a dose of 1000 mg/m 2 once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid) however a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half life (T½) of a single dose of 1000 mg/m 2 was 1.5 hr ( 0.3 hr) and peak levels were reached in an average of 1.9hrs ( 0.3 hr). The half life was found to be independent of dose, but a trend towards increasing half life following multiple dosing was observed. Histone H4 4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. ConclusionsHigh doses of oral belinostat, up to 1000 mg/m 2 bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat.

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Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies

Cited by 130 publications

References 36 publications

Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models

Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models

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

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

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