Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vorinostat (suberoylanilide hydroxamic acid) is the prototype of a family of hybrid polar compounds that can induce growth arrest in transformed cells and shows promise for the treatment of cancer. Vorinostat specifically binds to and inhibits the activity of histone deacetylases resulting in acetylation of nucleosomal histones and an activation of gene transcription. Because histone deacetylases modulate chromatin structure and gene expression, both of which can influence radioresponse, this study was designed to examine the capacity of Vorinostat to influence radiation response in human tumor cells and investigate the mechanism underlying these interactions. Vorinostat induced hyperacetylation of histone H4 in a dose-dependent manner. We tested its ability to radiosensitize three human tumor cell lines (A375, MeWo, and A549) using clonogenic cell survival assays. Clonogenic cell survival assay showed that Vorinostat significantly radiosensitized all three tumor cell lines, substantially reducing the surviving fraction at 2 Gy. We examined potential mechanisms that may contribute to the enhanced radiation response induced by Vorinostat. Vorinostat and radiation alone did not induce apoptosis in the melanoma cell line. However, enhanced apoptosis was observed when cells were exposed to both Vorinostat and radiation, suggesting that Vorinostat renders tumor cells more susceptible to radiation-induced apoptosis. Results from DNA damage repair analysis in cultured A375 cells showed that Vorinostat had a strong inhibitory effect on the nonhomologous end joining pathway after radiation. A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis. We also examined gamma-H2AX phosphorylation as a predictive marker of radiotherapy response to Vorinostat and observed that the combination of Vorinostat and radiation caused a prolongation of expression of DNA repair proteins such as gamma-H2AX. Overall, we conclude that Vorinostat enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation.
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PMID:Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. 1692 17

In our quest to understand why dimethyl sulfoxide (DMSO) can cause growth arrest and terminal differentiation of transformed cells, we followed a path that led us to discover suberoylanilide hydroxamic acid (SAHA; vorinostat (Zolinza)), which is a histone deacetylase inhibitor. SAHA reacts with and blocks the catalytic site of these enzymes. Extensive structure-activity studies were done along the path from DMSO to SAHA. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in tumor-bearing animals at concentrations not toxic to normal cells. SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death. In clinical trials, SAHA has shown significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application was approved by the US Food and Drug Administration for vorinostat for treatment of cutaneous T-cell lymphoma. More potent analogs of SAHA have shown unacceptable toxicity.
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PMID:Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. 1721 7

Vorinostat (suberoylanilide hydroxamic acid, SAHA) represents a new class of highly potent histone deacetylase (HDAC) inhibitors that cause growth arrest, differentiation, and apoptosis of many tumor types in vitro and in vivo. RUNX3, a gastric tumor suppressor, is epigenetically silenced in gastric cancer cells. This study investigates the role of RUNX3 in vorinostat-induced suppression of gastric cancer cell growth. RUNX3 was up-regulated by vorinostat in gastric cancer cell lines not expressing RUNX3. In terms of cell viability, the mean IC(50) of vorinostat in RUNX3-negative cells was significantly lower than that seen in RUNX3-positive cells, indicating that the former are more sensitive to vorinostat in terms of growth arrest than are RUNX3-positive lines. The mechanism underlying this difference was found to be reactivation of RUNX3 expression by vorinostat and concomitant increase in acetylated histone H3 in the promoter region of RUNX3. Using three RUNX3-negative cell lines, we determined the contribution of RUNX3 reactivation to growth inhibition and induction of apoptosis following treatment of cells with vorinostat and found that up-regulated RUNX3 was significantly responsible for tumor suppressive activities.
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PMID:Contribution of reactivated RUNX3 to inhibition of gastric cancer cell growth following suberoylanilide hydroxamic acid (vorinostat) treatment. 1727 7

Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Emu-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Emu-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents.
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PMID:Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. 1747 Jul 84

Recently, the role of transcriptional repression through epigenetic modulation in carcinogenesis has been clinically validated with several inhibitors of histone deacetylases and DNA methyltransferases. It has long been recognized that epigenetic alterations of tumor suppressor genes was one of the contributing factors in carcinogenesis. Inhibitors of histone deacetylase (HDAC) de-repress genes that subsequently result in growth inhibition, differentiation and apoptosis of cancer cells. Vorinostat (SAHA), romidepsin (depsipeptide, FK-228), belinostat (PXD101) and LAQ824/LBH589 have demonstrated therapeutic benefit as monotherapy in cutaneous T-cell lymphoma (CTCL) and have also demonstrated some therapeutic benefit in other malignancies. The approval of the HDAC inhibitor vorinostat (Zolinzatrade mark) was based on the inherent sensitivity of this type of lymphoma to alterations in acetylation patterns that resulted in the induction of repressed apoptotic pathways. However, the full potential of these inhibitors (epigenetic modulators) is still on the horizon, as the true breadth of their utility as anti-cancer agents will be determined by the careful analysis of gene expression changes generated by these inhibitors and then combined with conventional chemotherapy to synergistically improve response and toxicity for an overall enhanced therapeutic benefit to the patient. The question that must be considered is whether the current HDACIs are being utilized to their fullest potential in clinical trials based on their mechanism-based alterations in disease processes.
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PMID:HDAC inhibitors: clinical update and mechanism-based potential. 1749 67

Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA, Vorinostat), valproic acid (VPA), and FK228 are members of a relatively novel class of small molecular weight chemicals that have high antineoplastic activity. They cause growth inhibition and apoptosis specifically in tumor cells, and they act also as chemo- and radio-sensitizers. In the present study, the potential of SAHA and VPA to induce resistance was studied. To that aim HDAC inhibitor-resistant sublines were generated by stepwise exposure of colon tumor cells to increasing concentrations of these compounds. Clonogenic data demonstrated that the SAHA- and VPA-induced sublines were 2-fold resistant to these compounds. This resistance was non-reversible, as it was maintained even when the sublines were cultured in the absence of SAHA or VPA. The SAHA- and VPA-induced resistant sublines were also stably cross-resistant to VPA and SAHA, respectively, but retained sensitivity against non-HDAC inhibitor-type anticancer agents. The SAHA-induced resistance correlated with loss of the G2/M checkpoint but it was not accompanied by reduced induction of the endogenous cell cycle inhibitors p21 and p27. Furthermore, SAHA-induced resistance was not due to reduced apoptosis, and it was neither dependent on MDR expression nor was it due to increased expression of HDAC1 and HDAC3. Taken together, these data demonstrate the potential of SAHA and VPA to induce resistance. This resistance was not dependent on MDR expression, did not involve MMR, and seemed to underlie a mechanism that differs from that underlying the previously observed FK228-induced resistance. The finding that SAHA and VPA induce only modest resistance despite continuous treatment and that the resistance is MDR-independent suggests a preference for these two drugs over FK228 for use in combination treatment with classic anticancer agents.
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PMID:The histone deacetylase inhibitors suberoylanilide hydroxamic (Vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells. 1767 92

Over the last two decades, preclinical and clinical research has implicated epigenetic alterations in the pathogenesis and progression of cancer. Epigenetic changes, involving both DNA methylation and alterations in chromatin structure, are associated with the inhibition of transcription of key cell regulatory genes that, under normal conditions, control the cell cycle and initiate apoptotic cell death in neoplastic cells. Drugs have been developed with functional effects, including DNA hypomethylation and histone acetylation, that serve to restore the normal transcription of cell regulatory genes (eg, tumor suppressor genes). DNA hypomethylating agents, such as azacitidine (Vidaza), and histone deacetylase inhibitors such as vorinostat (Zolinza) have been approved in the US for the treatment of cancer, reinforcing the importance of these pathways in the biology of this disease. Current research involves combining these classes of agents and identifying new drug targets within the growing family of epigenetic enzymes.
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PMID:Epigenetic alterations and cancer: new targets for therapy. 1789 89

This phase II trial was initiated to assess the efficacy and safety of oral vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Eligible patients must have recurrent and/or metastatic head and neck cancer unresponsive to or intolerant of conventional chemotherapy. Patients must have measurable disease, adequate hematologic, hepatic, and renal function, and be able to swallow capsules. Four or more weeks must have elapsed since prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy, and patients must have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Thirteen patients were enrolled (9 males); 1 withdrew consent prior to starting therapy. Twelve patients received oral vorinostat 400 mg once daily and were evaluable for response. The median age was 54 years (range 40-82). All patients had received prior chemotherapy (including 10 with platinum- or taxane-based combination therapy), and 9 had prior radiation therapy. No confirmed partial or complete responses were observed. One unconfirmed partial response was seen. Three patients had stable disease ranging from 9 to 26 weeks. Nine patients discontinued due to progressive disease, two withdrew consent, and one discontinued therapy for grade 3 anorexia. Grades 3-4 drug-related toxicities included thrombocytopenia (n=3), anorexia (n=2), and dehydration (n=2). Oral vorinostat 400 mg qd was generally well tolerated but did not demonstrate efficacy as defined by tumor response in this small group of heavily pre-treated patients.
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PMID:Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. 1796 Mar 24

Histone deacetylase inhibitors (HDI) are a promising new approach to the treatment of cancer. HDIs have been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of transformed cell lines; inhibit tumor growth in animal models; and show antitumor activity in clinical trials. Vorinostat, which has shown clinical responses in approximately 30% of patients with advanced cutaneous T-cell lymphoma, is the first HDI approved for the treatment of cancer, and it is currently being evaluated in other indications. A better understanding of the molecular determinants of resistance to HDIs may provide the basis for therapeutic combinations with improved clinical efficacy. Poor response to treatment could be linked to systemic factors like pharmacokinetics or to tumor-specific factors both at the level of the malignant cells (tumor intrinsic) or the tumor microenvironment. This review focuses on the tumor intrinsic mechanisms of drug resistance (excluding mechanism of acquired resistance due to chronic exposure). In particular, attention is given to selected mechanisms that are relevant across chemical classes of HDIs and that can aid in the design of rational combination strategies.
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PMID:Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. 1809 1

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.
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PMID:MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. 1841 90


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