A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL

Abstract.Although the therapeutic efficacy of valproic acid (VPA) has been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical utility. The present study focused on the development of combined molecular targeted therapies using VPA and proteasome inhibitors (PIs: MG132, PI-1 and PR-39) to determine whether this combination of treatments has synergistic anticancer and chemosensitizing effects against colorectal cancer. Furthermore, the potential molecular mechanisms of action of the VPA/PI combinations were evaluated. The effects of VPA in combination with PIs on the growth of colorectal cancer cells were assessed with regard to proliferation, cell cycle, apoptosis, reactive oxygen species (ROS) generation and the expression of genes that control the cell cycle, apoptosis and pro-survival/stress-related pathways. Treatment with combinations of VPA and PIs resulted in an additive/synergistic decrease in colorectal cancer cell proliferation compared to treatment with VPA or PIs alone. The combination treatment was associated with a synergistic increase in apoptosis and in the number of cells arrested in the S phase of the cell cycle. These events were associated with increased ROS generation, pro-apoptotic gene expression and stress-related gene expression. These events were also associated with the decreased expression of anti-apoptotic genes and pro-survival genes. The combination of VPA with MG132 or PI-1 enhanced the chemosensitivity of the SW1116 (29-185-fold) and SW837 (50-620-fold) colorectal cancer cells. By contrast, the combination of VPA/PR-39 induced a pronounced increase in the chemosensitivity of the SW837 (16-54-fold) colorectal cancer cells. These data provide a rational basis for the clinical use of this combination therapy for the treatment of colorectal cancer. IntroductionHistone deacetylase (HDAC) activity has been shown to be upregulated in cancer cells. It is considered that this upregulation results in the repression of tumor suppressor gene products, such as p53, rendering HDACs an attractive drug target. In cell culture models, HDAC inhibitors (HDACIs) have been shown to decrease proliferation rates, induce apoptosis and induce autophagy-related cell death in several cancer cell lines. Due to their relative specificity toward cancer cells, HDACIs represent a new class of cancer treatment agents that are generally well tolerated (1).Short-chain fatty acids, such as butyric and valproic acid (VPA) were the first HDACIs to be identified as tumor growth inhibitors and inducers of apoptosis both in vitro and in vivo. However, they were found to have low potency (2). Despite such weak in vitro activity, the anticancer effects of VPA have been investigated in preclinical models of skin, breast, colon, prostate and small cell lung cancer, and the drug is currently being used in phase I-III clinical trials (3). However, the therapeutic doses of VPA are very high and cause side-effects severe enough to limit its usage.Despite ...

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“…6-10 and Tables I and II). These results are consistent with findings in other malignancies (59,65,66).…”

Section: Discussionsupporting

confidence: 93%

“…One hypothesis to explain the development of chemoresistance is an acquired resistance of the tumor cells to apoptosis (59), allowing tumors to withstand high levels of chemotherapy. Tumor cells that are resistant to apoptosis also exhibit an increased proliferative capacity.…”

Section: Discussionmentioning

confidence: 99%

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Abaza

Bahman

Al‐Attiyah

2014

International Journal of Molecular Medicine

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“…CG has been studied for treatment of cancers such as non-small cell lung cancer [22] and prostate cancer [23], as well as induction of cell death such as lung and splenic apoptosis [24] and clonogenic cell death [25]. Our results show that CG has a beneficial effect on prevention of hypertension, cardiac hypertrophy, and fibrosis in DOCA-induced hypertensive rats.…”

Section: Discussionmentioning

confidence: 68%

Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

Lee

Song

Lee

et al. 2016

Korean J Physiol Pharmacol

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CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

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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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A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL

Cited by 32 publications

References 29 publications

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

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

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