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Intrinsic and Extrinsic Factors That Influence Epigenetics
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Ivan Nalvarte, Joëlle Rüegg, Carlos Guerrero-Bosagna
The first pharmacological agent used to deliberately alter the epigenome was the demethylating agent 5-AzaC. 5-AzaC was initially tested as a treatment against leukemia in mice (87) and is currently approved by the FDA (since 2004) for the chemotherapeutical treatment of the myelodysplastic syndrome (88). In addition to 5-AzaC, there are currently a number of other epigenetic drugs approved for clinical use by the FDA (89): Decitabine (5-aza-2′-deoxycytidine) is also a hypomethylating agent with similar therapeutic applications as 5-AzaC for the treatment of myelodysplastic syndrome; Tranylcypromine and phenelzine are lysine demethylase inhibitors initially approved as anti-depressants, but currently also tested for cancer treatment; Trichostatin-A, Vorinostat, Panobinostat, and Belinostat are HDAC inhibitors (of the hydroxamic acids group) employed in the treatment of lymphoma and leukemia; Mocetinostat is an HDAC inhibitor from the benzamides group also employed for the treatment of myelodysplastic syndrome; Romidepsin is an HDAC I and II inhibitor with cyclic tetrapeptide antibiotic and antineoplastic activity approved for the treatment of patients with cutaneous T-cell lymphoma, used after they have been administered with systemic therapy (89). In addition, three epigenetic drugs based on the action of miRNAs have entered clinical trials: Miravirsen and RG-101 for the treatment of hepatitis C, and MRX34 for the treatment of cancer (89). Table 6.2 summarizes the current status of pharmacological agents that alter the epigenome.
Advances in Hodgkin’s lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors
Published in Expert Opinion on Pharmacotherapy, 2023
Thuy Ho, Cara Coleman, Palak Shah, Victor Yazbeck
Whereas the above agents are pan-HDAC inhibitors, mocetinostat (MGCD0103) selectively inhibits class I and IV enzymes, specifically HDAC1, but also has activity against HDAC2, HDAC3, and HDAC11 [45]. It also belongs to a different chemical group, the benzamides [34]. Early in vitro studies confirmed the antiproliferative activity of mocetinostat in various solid and hematologic human cancer cell lines, including Hodgkin lymphoma, via cell cycle arrest in the G1 and G2-M phases and induction of p21 [45]. Mocetinostat also leads to apoptosis via caspase-dependent pathways, by increased expression of pro-apoptotic microRNAs (miR-31), and suppression of the anti-apoptotic protein E2F6 [46]. Mocetinostat has more potent antiproliferative effects than vorinostat and is more selective: lack of antiproliferative activity against normal (non-cancer) human cells, such as fibroblasts, whereas vorinostat exhibits strong antiproliferative effects against fibroblasts. Mocetinostat also inhibits human tumor growth in mouse xenograft models [47]. Like vorinostat and panobinostat, mocetinostat has also been shown to influence the tumor microenvironment by decreasing T regulatory cells and increasing CD8+ cytotoxic T cells. In Hodgkin lymphoma cell lines, while mocetinostat causes apoptosis and downregulation of CD30, it also leads to increased expression of the inflammatory cytokine TNF-α, resulting in NF-KB activation [48]. Therefore, inhibition of NF-KB activation by the proteasome inhibitor bortezomib has demonstrated synergistic activity with mocetinostat [49].
Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1+ triple negative breast cancer cells
Published in OncoImmunology, 2019
Nishant Mohan, Salman Hosain, Jun Zhao, Yi Shen, Xiao Luo, Jiangsong Jiang, Yukinori Endo, Wen Jin Wu
Given that only 10% of patients with metastatic disease respond to single-agent activity of immune checkpoint inhibitors,7 current efforts are being invested in developing immunotherapy/chemotherapy combinations that can further enhance responses and overcome resistance to checkpoint inhibitors. For this purpose, we extended our investigation to screen novel combination approaches to amplify the anti-tumor efficacy of ATE in TNBC models. Recent studies have shown histone deacetylase (HDAC) inhibitors can improve the anti-tumor activity of immunotherapies by increasing PD-L1 expression levels.22,23 First, we confirmed that mocetinostat (moce), a HDAC inhibitor, in combination with ATE increased PD-L1 expression in MDA-MB-231 and BT-20 cells (Figure 4(a)). However, the expression of PD-L1 was not increased in PD-L1− MDA-MB-468 cells when treated with ATE and moce (Figure 4(a)). As shown in Figure 4(b), combination of ATE + moce significantly inhibited cell growth in T cell co-incubated MDA-MB-231 and BT-20 cells, but not in MDA-MB-468 cells, compared with ATE or moce treatment alone. These data suggest that moce-mediated enrichment of PD-L1 can promote tumor recognition through T cell receptor thus allowing ATE to elicit its anti-tumor activity against TNBC cells.
Biomarkers of aggressiveness in genitourinary tumors with emphasis on kidney, bladder, and prostate cancer
Published in Expert Review of Molecular Diagnostics, 2018
Alessia Cimadamore, Silvia Gasparrini, Matteo Santoni, Liang Cheng, Antonio Lopez-Beltran, Nicola Battelli, Francesco Massari, Francesca Giunchi, Michelangelo Fiorentino, Marina Scarpelli, Rodolfo Montironi
Recently, Duex and colleagues found that the great majority (83%) of urothelial carcinomas have mutations in chromatin remodeling genes. In particular, two chromatin remodeling genes, EP300 and its paralog, CREBBP, harbor missense mutations in the histone-acetyltransferase (HAT) domain, a very important site for the acetylation of histones involved in regulating the opening of the chromatin for gene transcription. The functional consequences of each HAT missense mutation can be predicted by the Mutation Assessor software. The loss of HAT activity has been associated with more aggressive cancer in four patient data sets. Thus, these results also have implications for therapy. Indeed, the response to treatment with mocetinostat, a histone deacetylase (HDAC) inhibitor, depends on HAT activity [33].