85 results on '"Minucci, Saverio"'
Search Results
2. Histone deacetylases and epigenetic therapies of hematological malignancies
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Mercurio, Ciro, Minucci, Saverio, and Pelicci, Pier Giuseppe
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HISTONE deacetylase , *EPIGENESIS , *ACUTE myeloid leukemia , *CHROMATIN , *HEMATOLOGY , *GENETIC transcription , *HODGKIN'S disease - Abstract
Abstract: Histone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acetylation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to determine changes in gene transcription and to induce a plethora of biological effects ranging from cell death induction, to differentiation, angiogenesis inhibition or modulation of immune responses. The impressive anticancer activity observed in both in vitro and in vivo cancer models, together with their preferential effect on cancer cells, have led to a huge effort into the identification and development of HDACi with different characteristics. To date, several clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin lymphoma (HL) and myeloid malignancies. Several agents are also beginning to be tested in combination therapies, either as chemo sensitizing agents in association with standard chemotherapy drugs or in combination with DNA methyltransferase inhibitors (DNMTi) in the context of the so-called “epigenetic therapies”, aimed to revert epigenetic alterations found in cancer cells. Herein, we will review HDACi data in hematological malignancies questioning the molecular basis of observed clinical responses, and highlighting some of the concerns raised on the use of these drugs for cancer therapy. [Copyright &y& Elsevier]
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- 2010
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3. Epigenetic therapies in haematological malignancies: Searching for true targets
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Altucci, Lucia and Minucci, Saverio
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ACUTE myeloid leukemia treatment , *EPIGENESIS , *TARGETED drug delivery , *CANCER cell proliferation , *ENZYME inhibitors , *HISTONE deacetylase , *COMBINATION drug therapy , *PREVENTION - Abstract
Abstract: Epigenetic alterations complement genetic mutations as a molecular mechanism leading to cell transformation, and maintenance of the cancer phenotype. Of note, they are reversible by pharmacological manipulation of the enzymes responsible for chromatin modification: indeed, epigenetic drugs (histone deacetylase inhibitors and DNA demethylating agents) are currently on the market, inducing proliferative arrest and death of tumor cells. These drugs, however, have been effective only in a few tumor types: the lack of consistent clinical results is mainly due to their use in a poorly targeted approach, since the epigenetic alterations present in cancer cells are mostly unknown. In a few cases (notably, leukemias expressing RAR and MLL fusion proteins), the molecular mechanisms underlying tumor-selective and tumor-specific epigenetic alterations have started to be deciphered. These studies are revealing a dazzling complexity in the mechanisms leading to alterations of the epigenome, and the need of combination therapies targeting different chromatin modifiers to reach an effective reversion of epigenetic alterations. [Copyright &y& Elsevier]
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- 2009
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4. Epigenomic profiling of cancer cells
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Gargiulo, Gaetano and Minucci, Saverio
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METHYLATION , *HISTONES , *CANCER cells , *DNA , *EPIGENESIS , *CHROMATIN , *CELL nuclei - Abstract
Abstract: DNA methylation, post-translational modifications of histones and high order organization of chromatin in cell nuclei are the components of the epigenome. Epigenetic regulation of gene expression is specific for each cell type, within different tissues, according to stages of development and (in the adult organism) of differentiation. Almost invariably, this regulation is altered in disease states, including cancer. The complete understanding of the identity of the epigenome of cancer has been so far hampered, due to the technical limitations and costs of the genome-wide analyses required. The recent development of next generation sequencing (NGS) technologies, however, holds the promise of fast, reliable and cost-effective analyses. Here we review the main approaches employed thus far to identify altered epigenetic patterns in cancer cells, and analyse how they are predicted to evolve in the scenario of the ultra high-throughput (UHT) screenings. [Copyright &y& Elsevier]
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- 2009
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5. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.
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Minucci, Saverio and Pelicci, Pier Giuseppe
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HISTONE deacetylase , *AMIDASES , *DRUG development , *CANCER treatment , *CLINICAL trials , *CLINICAL medicine research , *CARCINOGENESIS , *MEDICAL protocols - Abstract
Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols. [ABSTRACT FROM AUTHOR]
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- 2006
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6. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.
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Göttlicher, Martin, Minucci, Saverio, Zhu, Ping, Krämer, Oliver H., Schimpf, Annemarie, Giavara, Sabrina, Sleeman, Jonathan P., Lo Coco, Francesco, Nervi, Clara, Pelicci, Pier Giuseppe, and Heinzel, Thorsten
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VALPROIC acid , *HISTONE deacetylase inhibitors , *CELL differentiation , *CELL transformation , *ACUTE myeloid leukemia , *ANIMAL experimentation - Abstract
Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well‐tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC‐dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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7. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.
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Göttlicher, Martin, Minucci, Saverio, Ping Zhu, Krämer, Oliver H., Schimpf, Annemarie, Giavara, Sabrina, Sleeman, Jonathan P., lo Coco, Francesco, Nervi, Clara, Pelicci, Pier Giuseppe, and Heinzel, Thorsten
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VALPROIC acid , *HISTONE deacetylase , *CANCER treatment , *LEUKEMIA , *METASTASIS , *CELL differentiation - Abstract
Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the welt-tolerated antiepileptic drug vaiproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Vaiproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, trans- formed hematopoietic progenitor cells and teukemic blasts from acute myeloid leukemia patients. Moreover, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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8. Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?
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Minucci, Saverio, Nervi, Clara, Coco, Francesco Lo, and Pelicci, Pier Giuseppe
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HISTONE deacetylase , *MOLECULES , *ACUTE leukemia , *CARCINOGENESIS , *LEUKEMIA treatment - Abstract
Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias. Oncogene (2001) 20, 3110–3115. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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9. A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells.
- Author
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Minucci, Saverio and Horn, Valerie
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ACETYLATION , *HISTONES , *RETINOIDS - Abstract
Examines the effects of trichostatin A (TSA), a specific inhibitor of histone deacetylase, on P19 embryonal carcinoma cells, in an effort to understand the role of histone acetylation in retinoid-dependent transcription. Methodology of the study; Results obtained; What the results indicate.
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- 1997
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10. Determinants of Oncogenic Transformation in Acute Promyelocytic Leukemia: The Hetero-Union Makes the Force
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Minucci, Saverio and Pelicci, Pier Giuseppe
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LEUKEMIA , *TRETINOIN , *RETINOIDS , *DNA-binding proteins , *PROTEINS , *OLIGOMERS - Abstract
Acute promyelocytic leukemia (APL) is caused by chromosomal translocations that involve the retinoic acid receptor α (RAR) and several other genes to yield X-RAR fusion proteins. Unlike wild-type RARs, which require heterodimerization with the retinoid X receptor (RXR) for their function as DNA-binding transcriptional regulators, X-RAR fusion proteins bind DNA and deregulate transcription as homo-oligomers. In this issue of Cancer Cell, however, Zeisig et al. and Zhu et al. show that RXR recruitment is a critical determinant for the transforming potential of oligomeric X-RAR fusion proteins and explore the possibility for targeted interventions in APL with either RAR or RXR ligands. [Copyright &y& Elsevier]
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- 2007
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11. Comparing apples with oranges: Studying LSD1 inhibitors in cellular assays.
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Minucci, Saverio and Abdel-Aziz, Amal Kamal
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LYSINE specific demethylase 1 , *HISTONE demethylases , *COLONY-forming units assay - Published
- 2019
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12. Mechanisms of Selective Anticancer Action of Histone Deacetylase Inhibitors.
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Insinga, Alessandra, Minucci, Saverio, and Pelicci, Pier Giuseppe
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- 2005
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13. Cabozantinib in neuroendocrine tumors: tackling drug activity and resistance mechanisms.
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Cella, Chiara Alessandra, Cazzoli, Riccardo, Fazio, Nicola, De Petro, Giuseppina, Gaudenzi, Germano, Carra, Silvia, Romanenghi, Mauro, Spada, Francesca, Grossi, Ilaria, Pallavicini, Isabella, Minucci, Saverio, and Vitale, Giovanni
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NEUROENDOCRINE tumors , *CELL migration , *DRUG resistance , *CELL cycle , *PROTEIN-tyrosine kinase inhibitors - Abstract
Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing in vitro and in vivo models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescenceactivated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both in vitro and in vivo models. On this basis, we envisage future research to further investigate along these promising lines. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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14. DNA binding modes of leukemia oncoproteins.
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Minucci, Saverio
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TUMOR proteins , *DNA-binding proteins , *ACUTE myeloid leukemia , *ACUTE myeloid leukemia treatment , *DEREGULATION , *GENE therapy , *THERAPEUTICS - Abstract
The article discusses the DNA-binding mechanisms or approaches of leukemia oncoproteins in acute myeloid leukemias (AMLs). Topics discussed include the leukemia-associated oncoproteins action mode, the deregulation of gene expression, and the binding transcription factors to their binding sites for upregulation.
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- 2016
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15. Tackling Oxidative Stress by a Direct Route: A New Job for HDAC Inhibitors?
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Sartori, Luca and Minucci, Saverio
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OXIDATIVE stress , *HISTONE deacetylase inhibitors , *HYDROXAMIC acids , *CHEMICAL reactions , *HYDROGEN peroxide , *WATER - Abstract
Olson et al. (2015) propose that some hydroxamic acid-based small molecules, already in clinical use as histone deacetylase inhibitors, may protect against oxidative stress through a direct chemical reaction of dismutation of hydrogen peroxide into water. [ABSTRACT FROM AUTHOR]
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- 2015
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16. A novel autophagy-independent, oncosuppressive function of BECN1: Degradation of MCL1.
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Elgendy, Mohamed and Minucci, Saverio
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- 2015
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17. Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia.
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Zhai, Yanan, Singh, Prashant, Dolnik, Anna, Brazda, Peter, Atlasy, Nader, del Gaudio, Nunzio, Döhner, Konstanze, Döhner, Hartmut, Minucci, Saverio, Martens, Joost, Altucci, Lucia, Megchelenbrink, Wout, Bullinger, Lars, and Stunnenberg, Hendrik G.
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ACUTE myeloid leukemia , *HEMATOPOIETIC stem cells , *SOMATIC mutation , *PRELEUKEMIA , *HEMATOPOIETIC system , *CELL migration - Abstract
Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. Methods: Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. Results: scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. Conclusions: In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Self-renewal of tumor cells: epigenetic determinants of the cancer stem cell phenotype.
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Ravasio, Roberto, Ceccacci, Elena, and Minucci, Saverio
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CANCER stem cells , *PHENOTYPIC plasticity , *EPIGENOMICS , *CANCER genetics , *HETEROGENEITY - Abstract
Among the functional subpopulations that coexist within the tumor, ‘cancer stem cells’ are characterized by increased self-renewal and the ability to derive all of the other subpopulations of tumor cells (‘bulk’). The functional heterogeneity among cancer stem cells and bulk cells must reflect distinct cellular epigenetic landscapes, but — due to the difficulty to isolate bona fide cancer stem cells with a high degree of purity — those different epigenetic landscapes, and the molecular mechanisms underlying them, remain largely unknown. Cues of intratumor phenotypic plasticity complicate the interpretation of the cancer stem cell phenotype: we contend that, however, the concept of cancer stem cell has crucial therapeutic implication, and remains a key target for the exploration of the cancer epigenome. [ABSTRACT FROM AUTHOR]
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- 2016
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19. Sex and cancer immunotherapy: Current understanding and challenges.
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Pala, Laura, De Pas, Tommaso, Catania, Chiara, Giaccone, Giuseppe, Mantovani, Alberto, Minucci, Saverio, Viale, Giuseppe, Gelber, Richard D., and Conforti, Fabio
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IMMUNE checkpoint inhibitors , *IMMUNOTHERAPY , *IMMUNE response - Abstract
Recent evidence highlights patients' sex relevance in antitumor immune response through a complex interaction—among hormones, genes, behaviors, and the microbiome—that affects both innate and adaptive immune functions, as well as immune evasion mechanisms. These complex interactions ultimately influence the efficacy and toxicity of immune checkpoint inhibitors in solid tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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20. Epigenetic alterations in acute myeloid leukemias.
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Mehdipour, Parinaz, Santoro, Fabio, and Minucci, Saverio
- Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease for which the standard treatment with cytotoxic chemotherapy has remained largely unchanged for over four decades, with unfavorable clinical results. Epigenetic alterations have been described in several AMLs, and in some cases their origin has been studied in detail mechanistically (such as in acute promyelocytic leukemia, caused by the promyelocytic leukemia–retinoic acid receptor-a fusion protein). Recently, the advent of massive parallel sequencing has revealed that > 70% of AML cases have mutations in DNA methylation- related genes or mutations in histone modifiers, showing that epigenetic alterations are key players in the development of most, if not all, AMLs, and pointing to the exploitation of new molecular targets for more efficacious therapies. This review provides a brief overview of the latest findings on the characterization of the epigenetic landscape of AML and discusses the rationale for the optimization of epigenetic therapy of AML. [ABSTRACT FROM AUTHOR]
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- 2015
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21. SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation.
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Jevtic, Zivojin, Matafora, Vittoria, Casagrande, Francesca, Santoro, Fabio, Minucci, Saverio, Garre', Massimilliano, Rasouli, Milad, Heidenreich, Olaf, Musco, Giovanna, Schwaller, Jürg, and Bachi, Angela
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CELL transformation , *CHIMERIC proteins , *ACUTE myeloid leukemia , *HEMATOPOIETIC stem cells , *MYELOID cells , *PROGENITOR cells - Abstract
Background: Acute myeloid leukemia (AML) is characterized by accumulation of aberrantly differentiated hematopoietic myeloid progenitor cells. The karyotyping-silent NUP98-NSD1 fusion is a molecular hallmark of pediatric AML and is associated with the activating FLT3-ITD mutation in > 70% of the cases. NUP98-NSD1 fusion protein promotes myeloid progenitor self-renewal in mice via unknown molecular mechanism requiring both the NUP98 and the NSD1 moieties. Methods: We used affinity purification coupled to label-free mass spectrometry (AP-MS) to examine the effect of NUP98-NSD1 structural domain deletions on nuclear interactome binding. We determined their functional relevance in NUP98-NSD1 immortalized primary murine hematopoietic stem and progenitor cells (HSPC) by inducible knockdown, pharmacological targeting, methylcellulose assay, RT-qPCR analysis and/or proximity ligation assays (PLA). Fluorescence recovery after photobleaching and b-isoxazole assay were performed to examine the phase transition capacity of NUP98-NSD1 in vitro and in vivo. Results: We show that NUP98-NSD1 core interactome binding is largely dependent on the NUP98 phenylalanine-glycine (FG) repeat domains which mediate formation of liquid-like phase-separated NUP98-NSD1 nuclear condensates. We identified condensate constituents including imitation switch (ISWI) family member SMARCA5 and BPTF (bromodomain PHD finger transcription factor), both members of the nucleosome remodeling factor complex (NURF). We validated the interaction with SMARCA5 in NUP98-NSD1+ patient cells and demonstrated its functional role in NUP98-NSD1/FLT3-ITD immortalized primary murine hematopoietic cells by genetic and pharmacological targeting. Notably, SMARCA5 inhibition did not affect NUP98-NSD1 condensates suggesting that functional activity rather than condensate formation per se is crucial to maintain the transformed phenotype. Conclusions: NUP98-NSD1 interacts and colocalizes on the genome with SMARCA5 which is an essential mediator of the NUP98-NSD1 transformation in hematopoietic cells. Formation of NUP98-NSD1 phase-separated nuclear condensates is not sufficient for the maintenance of transformed phenotype, which suggests that selective targeting of condensate constituents might represent a new therapeutic strategy for NUP98-NSD1 driven AML. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. SILAC-based proteomic analysis to dissect the 'histone modification signature' of human breast cancer cells.
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Cuomo, Alessandro, Moretti, Simona, Minucci, Saverio, and Bonaldi, Tiziana
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PROTEOMICS , *CANCER cells , *BREAST cancer , *POST-translational modification , *HISTONES , *CELL culture , *MASS spectrometry , *CHROMATIN - Abstract
In living cells, the N-terminal tails of core histones, the proteinaceous component of nucleosomes, are subjected to a range of covalent post-translational modifications (PTMs), which have specific roles in modulating chromatin structure and function. A growing body of evidence suggests that deregulation of histone modification patterns, upstream or downstream of DNA methylation, is a critical event in cancer initiation and progression. However, a comprehensive description of how histone modifications, singly or in combination, is disrupted in transformed cells is missing; consequently the issue whether and how specific changes in histone PTMs patterns correlate to particular tumor features is still elusive. In the present study, we focused on human breast cancer and comprehensively analyzed PTMs on histone H3 and H4 from four cancer cell lines (MCF7, MDA-MB231, MDA-MB453 and T-47D), in comparison with normal epithelial breast cells. We performed high-resolution mass spectrometry analysis of histones, in combination with stable isotope labeling with amino acids in cell culture (SILAC), to quantitatively track the modification changes in cancer cells, as compared to their normal counterpart. Our investigation focuses on lysine acetylation and methylation on fourteen distinct sites in H3 and H4. We observed significant changes for several modifications in cancer cells: while in a few cases those modifications had been previously described as a hallmark of human tumors, we could identify novel modifications, whose abundance is significantly altered in breast cancer cells. Overall, these modifications may represent part of a 'breast cancer-specific epigenetic signature', with implications in the characterization of histone-related biomarkers. This work demonstrates that SILAC-based proteomics is a powerful tool to study qualitatively and quantitatively histone PTMs patterns, contributing significantly to the comprehension of epigenetic phenomena in cancer biology. [ABSTRACT FROM AUTHOR]
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- 2011
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23. Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer
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Botrugno, Oronza Antonietta, Santoro, Fabio, and Minucci, Saverio
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ENZYME inhibitors , *HISTONE deacetylase , *CELL differentiation , *EPIGENESIS , *GENE expression , *GENETIC regulation , *ANTINEOPLASTIC agents , *CANCER cells - Abstract
Abstract: Absent or altered differentiation is one of the major features of cancer cells. Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been documented in several types of cancers, leading to the development of HDAC inhibitors (HDACi) as anti-tumor drugs. In vitro and in vivo experimental evidences show that HDACi are able to resume the process of maturation in undifferentiated cancer cells, justifying their introduction as differentiating agents in several clinical trials. Modulation of cell fate by HDACi is observed at several levels, including the stem cell compartment: HDACi can act both on cancer stem cells, and with the rest of the tumor cell mass, leading to complex biological outputs. As a note of caution, when used as single agent, HDACi show only a moderate and limited biological response, which is augmented in combinatorial therapies with drugs designed against other epigenetic targets. The optimal employment of these molecules may be therefore in combination with other epigenetic drugs acting against the set of enzymes responsible for the set-up and maintenance of epigenetic information. [Copyright &y& Elsevier]
- Published
- 2009
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24. PML NBs associate with the HMre11 complex and p53 at sites of irradiation induced DNA damage.
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Carbone, Roberta, Pearson, Mark, Minucci, Saverio, and Pelicci, Pier Guiseppe
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PROTEINS , *FIBROBLASTS , *IONIZING radiation , *LEUKEMIA - Abstract
Presents a study that examined the modification of promyelocytic leukemia protein nuclear bodies (PML NB) and the recognition of sites of DNA breaks in human fibroblasts after ionizing radiation. Functions of PML NB; Background on PML; Characteristics of acute promyelocytic leukemia; Components of PML NB; Types of damage response pathways.
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- 2002
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25. Anticancer innovative therapy congress: Highlights from the 10th anniversary edition.
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De Santis, Francesca, Fucà, Giovanni, Schadendorf, Dirk, Mantovani, Alberto, Magnani, Luca, Lisanti, Michael, Pettitt, Stephen, Bellone, Matteo, Del Sal, Giannino, Minucci, Saverio, Eggermont, Alexander, Bruzzi, Paolo, Bicciato, Silvio, Conte, Pierfranco, Noberini, Roberta, Hiscott, John, De Braud, Filippo, Del Vecchio, Michele, and Di Nicola, Massimo
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LIPOSOMES , *CANCER stem cells , *MEDICAL personnel , *CELL communication , *CELL cycle , *IMMUNE system - Abstract
• Epigenetics, and in particular, chromatin modifiers. • Cancer metabolism. • Cancer stem cells. • Tumor cell signaling. • The immune system. During the Tenth Edition of the Annual Congress on "Anticancer Innovative Therapy" [Milan, 23/24 January 2020], experts in the fields of immuno-oncology, epigenetics, tumor cell signaling, and cancer metabolism shared their latest knowledge on the roles of i] epigenetics, and in particular, chromatin modifiers, ii] cancer metabolism, iii] cancer stem cells [CSCs], iv] tumor cell signaling, and iv] the immune system. The novel therapeutic approaches presented included epigenetic drugs, cell cycle inhibitors combined with ICB, antibiotics and other off-label drugs, small-molecules active against CSCs, liposome-delivered miRNAs, tumor-specific CAR-T cells, and T-cell–based immunotherapy. Moreover, important evidence on possible mechanisms of resistance to these innovative therapies were also discussed, in particular with respect to resistance to ICB. Overall, this conference provided scientists and clinicians with a broad overview of future challenges and hopes to improve cancer treatment reasonably in the medium-short term. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Leukemia-Associated Fusion Proteins.
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Insinga, Alessandra, Pelicci, Pier Giuseppe, and Minucci, Saverio
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- 2005
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27. Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for retinoic acid-induced differentiation.
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Ravasio, Roberto, Ceccacci, Elena, Nicosia, Luciano, Hosseini, Amir, Rossi, Pier Luigi, Barozzi, Iros, Fornasari, Lorenzo, Dal Zuffo, Roberto, Valente, Sergio, Fioravanti, Rossella, Mercurio, Ciro, Varasi, Mario, Mattevi, Andrea, Mai, Antonello, Pavesi, Giulio, Bonaldi, Tiziana, and Minucci, Saverio
- Subjects
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ACUTE myeloid leukemia , *HISTONE demethylases - Published
- 2020
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28. Preclinical models of breast cancer: Two-way shuttles for immune checkpoint inhibitors from and to patient bedside.
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Abdel-Aziz, Amal Kamal, Saadeldin, Mona Kamal, D'Amico, Paolo, Orecchioni, Stefania, Bertolini, Francesco, Curigliano, Giuseppe, and Minucci, Saverio
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THERAPEUTIC use of monoclonal antibodies , *PACLITAXEL , *BIOLOGICAL models , *BREAST tumors , *HOSPITAL patients , *MEMBRANE proteins , *MONOCLONAL antibodies , *NANOPARTICLES , *ROOMS , *ALBUMINS , *TREATMENT effectiveness , *CHEMICAL inhibitors - Abstract
The Food and Drug Administration has lately approved atezolizumab, anti-programmed death ligand 1 (PD-L1), to be used together with nanoparticle albumin-bound (nab) paclitaxel in treating patients with triple negative breast cancer (BC) expressing PD-L1. Nonetheless, immune checkpoint inhibitors (ICIs) are still challenged by the resistance and immune-related adverse effects evident in a considerable subset of treated patients without conclusive comprehension of the underlying molecular basis, biomarkers and tolerable therapeutic regimens capable of unleashing the anti-tumour immune responses. Stepping back to preclinical models is thus inevitable to address these inquiries. Herein, we comprehensively review diverse preclinical models of BC exploited in investigating ICIs underscoring their pros and cons as well as the learnt and awaited lessons to allow full exploitation of ICIs in BC therapy. • Triple-negative breast cancer patients are more likely to benefit from immune checkpoint inhibitors. • Preclinical models are indispensable for identifying biomarker and safe combo regimens. • Optimised preclinical models recapitulating human breast cancer heterogeneity are urged. • Preclinical integration of pharmacokinetic/pharmacodynamic modelling and scRNA profiling is fundamental. [ABSTRACT FROM AUTHOR]
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- 2019
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29. Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells.
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Roberti, Marinella, Schipani, Fabrizio, Bagnolini, Greta, Milano, Domenico, Giacomini, Elisa, Falchi, Federico, Balboni, Andrea, Manerba, Marcella, Farabegoli, Fulvia, De Franco, Francesca, Robertson, Janet, Minucci, Saverio, Pallavicini, Isabella, Di Stefano, Giuseppina, Girotto, Stefania, Pellicciari, Roberto, and Cavalli, Andrea
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PANCREATIC cancer treatment , *ANTINEOPLASTIC agents , *POLYMERASES , *POLY ADP ribose , *GENETIC mutation , *TARGETED drug delivery , *CANCER cells - Abstract
Abstract Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates. Graphical abstract Image 1 Highlights • Olaparib is a PARPi approved to treat ovarian cancer in BRCA2 defective patients. • BRCA2 mutations can be mimicked by disrupting Rad51-BRCA2 interaction. • A virtual screening allowed the identification of a triazole as small molecule PPI inhibitors. • Over 40 novel derivatives have computationally designed, synthesized, and tested. • 26 significantly increase the therapeutic power of olaparib in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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30. Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors.
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Milik, Sandra N., Abdel-Aziz, Amal Kamal, Lasheen, Deena S., Serya, Rabah A.T., Minucci, Saverio, and Abouzid, Khaled A.M.
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EPIDERMAL growth factor receptors , *PYRIMIDINES , *LAPATINIB , *CANCER cells , *CANCER treatment , *CANCER invasiveness - Abstract
In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3- d ]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC 50 values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC 50 values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC 50 of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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31. Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship.
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Vianello, Paola, Sartori, Luca, Amigoni, Federica, Cappa, Anna, Fagá, Giovanni, Fattori, Raimondo, Legnaghi, Elena, Ciossani, Giuseppe, Mattevi, Andrea, Meroni, Giuseppe, Moretti, Loris, Cecatiello, Valentina, Pasqualato, Sebastiano, Romussi, Alessia, Thaler, Florian, Trifiró, Paolo, Villa, Manuela, Botrugno, Oronza A., Dessanti, Paola, and Minucci, Saverio
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DRUG design , *HISTONE demethylases , *STRUCTURE-activity relationship in pharmacology , *GENETIC overexpression , *CANCER treatment - Abstract
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1, DOI 10.1021.acs.jmedchem.6b01018) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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32. Dual modulation of MCL-1 and mTOR determines the response to sunitinib.
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Elgendy, Mohamed, Abdel-Aziz, Amal Kamal, Renne, Salvatore Lorenzo, Bornaghi, Viviana, Procopio, Giuseppe, Colecchia, Maurizio, Kanesvaran, Ravindran, Chee Keong Toh, Bossi, Daniela, Pallavicini, Isabella, Perez-Gracia, Jose Luis, Lozano, Maria Dolores, Giandomenico, Valeria, Mercurio, Ciro, Lanfrancone, Luisa, Fazio, Nicola, Nole, Franco, Bin Tean Teh, Renne, Giuseppe, and Minucci, Saverio
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MTOR protein , *PROTEIN-tyrosine kinase inhibitors , *CELL-mediated cytotoxicity , *THERAPEUTIC use of monoclonal antibodies , *MYELOID leukemia - Abstract
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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33. Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity.
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Abdel-Aziz, Amal Kamal, Dokla, Eman M.E., Abouzid, Khaled A.M., and Minucci, Saverio
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ENDOPLASMIC reticulum , *ANTINEOPLASTIC agents , *UNFOLDED protein response , *CANCER cells , *HEAT shock proteins , *CELL cycle - Abstract
[Display omitted] Targeting endoplasmic reticulum (ER) stress presents a promising strategy in cancer therapy. We previously reported a series of 1,2,4-oxadiazole derivatives that induced the degradation of EGFR and c-Met which are implicated in tumorigenesis. Based on our previous SAR studies, herein, we report the discovery of EMD37, a novel 1,2,4-oxadiazole derivative, which demonstrated potent anticancer activity against NCI-60 cancer cell lines panel compared to its parent/lead compounds. Anti-proliferative assays revealed preferential cytotoxicity of EMD37 on cancer cells compared to normal cells. Delving deeper, we exploited unbiased genome-wide transcriptome profiling of EMD37-treated cancer cells. Gene Ontology and gene set enrichment analyses revealed that EMD37 promoted ER stress and unfolded protein response (UPR) machinery which was confirmed using RT-qPCR. Mining drug signature databases also confirmed the enrichment of the signature of canonical UPR inducers. Knocking down ER stress transcription factors compromised at least partly the anticancer activity of EMD37. Immunoblot analysis showed that EMD37 induced the accumulation of polyubiquitinated proteins and inhibited mTOR signaling. EMD37 induced G2/M cell cycle arrest and apoptosis of human cancer cells. Inhibiting apoptosis evidently abrogated the anticancer efficacy of EMD37. Altogether, this study introduces EMD37 as a novel ER inducer which warrants further investigation as a potentially relevant anti-cancer therapy. [ABSTRACT FROM AUTHOR]
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- 2022
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34. Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.
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Vianello, Paola, Botrugno, Oronza A., Cappa, Anna, Zuffo, Roberto Dal, Dessanti, Paola, Mai, Antonello, Marrocco, Biagina, Mattevi, Andrea, Meroni, Giuseppe, Minucci, Saverio, Stazi, Giulia, Thaler, Florian, Trifiró, Paolo, Valente, Sergio, Villa, Manuela, Varasi, Mario, and Mercurio, Ciro
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ANTINEOPLASTIC agents , *HISTONE demethylases , *TRANYLCYPROMINE , *PHARMACOKINETICS , *CANCER research - Abstract
We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic. [ABSTRACT FROM AUTHOR]
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- 2016
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35. Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors.
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Thaler, Florian, Moretti, Loris, Amici, Raffaella, Abate, Agnese, Colombo, Andrea, Carenzi, Giacomo, Fulco, Maria Carmela, Boggio, Roberto, Dondio, Giulio, Gagliardi, Stefania, Minucci, Saverio, Sartori, Luca, Varasi, Mario, and Mercurio, Ciro
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HISTONE deacetylase inhibitors , *ANTINEOPLASTIC agents , *DRUG synthesis , *HYDROXAMIC acid derivatives , *LIGAND binding (Biochemistry) , *IN vitro studies , *MOLECULAR models - Abstract
In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4′-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors. [ABSTRACT FROM AUTHOR]
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- 2016
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36. Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies.
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Matthews, Geoffrey M., Mehdipour, Parinaz, Cluse, Leonie A., Falkenberg, Katrina J., Wang, Eric, Roth, Mareike, Santoro, Fabio, Vidacs, Eva, Stanley, Kym, House, Colin M., Rusche, James R., Vakoc, Christopher R., Zuber, Johannes, Minucci, Saverio, and Johnstone, Ricky W.
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HISTONE deacetylase inhibitors , *ENZYME inhibitors , *LYMPHOID tissue , *LEUKEMIA treatment , *MYELOID leukemia , *BONE marrow diseases , *DISEASES , *THERAPEUTICS - Abstract
Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-approved for hematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACis in 3 genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine acute myeloid leukemias (MLL-AF9;NrasG12D; PML-RARα acute promyelocytic leukemia [APL] cells) and Eμ-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all 3 tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 overexpression, caspase inhibition, or knockout of Cdkn1a in Eμ-Myc lymphoma, and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Eμ-Myc lymphoma and induced differentiation in APL. Genetic codepletion of Hdac1 with Hdac2 was pro-apoptotic in Eμ-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells, suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that codepletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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37. Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models.
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Menna, Martina, Fiorentino, Francesco, Marrocco, Biagina, Lucidi, Alessia, Tomassi, Stefano, Cilli, Domenica, Romanenghi, Mauro, Cassandri, Matteo, Pomella, Silvia, Pezzella, Michele, Del Bufalo, Donatella, Zeya Ansari, Mohammad Salik, Tomašević, Nevena, Mladenović, Milan, Viviano, Monica, Sbardella, Gianluca, Rota, Rossella, Trisciuoglio, Daniela, Minucci, Saverio, and Mattevi, Andrea
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HISTONE demethylases , *ANTINEOPLASTIC agents , *CANCER cell proliferation , *HEMATOLOGIC malignancies , *LEUKEMIA , *BREAST , *CANCER cells - Abstract
LSD1 is a histone lysine demethylase proposed as therapeutic target in cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2 – 4 and 6 – 30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7 , 8 , and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 μM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone mark H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC 50 range, highlighting a crucial anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines. [Display omitted] • Novel potent and selective non-covalent LSD1 inhibitors are presented. • The crystal structure of LSD1 inhibitor 7 in complex with LSD1-CoREST unveils an unusual binding mode. • The most potent LSD1 inhibitors (7 , 8 and 29) display sub-micromolar antiproliferative effects in leukemia cells. • The same compounds inhibit breast cancer and rhabdomyosarcoma cell proliferation. • Functional assays confirm the inhibition of LSD1 at cellular level in both solid and hematological cancer cell lines. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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38. Insights into the design of inhibitors of the EGFR family with anticancer activity overcoming resistance: A case of optimizing thieno[2,3-d]pyrimidine-based EGFR inhibitors.
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Milik, Sandra N., Abdel-Aziz, Amal Kamal, El-Hendawy, Morad M., El-Gogary, Riham I., Saadeldin, Mona Kamal, Minucci, Saverio, Klein, Christian D., and Abouzid, Khaled A.M.
- Subjects
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EPIDERMAL growth factor receptors , *NON-small-cell lung carcinoma , *ANTINEOPLASTIC agents , *ERLOTINIB - Abstract
• Thieno[2,3- d ]pyrimidine-based dual EGFR/HER2 inhibitors were designed. • 12 compounds were prepared and tested against EGFR, HER2 and T790M/L858R. • Their anti-proliferative activities were assessed against relevant cancer cell lines. EGFR inhibitors have been in clinical use for the treatment of non-small cell lung cancer and breast cancer for years. However, generation after generation of the developed EGFR inhibitors have been met by clinical resistance. In an attempt to develop the next generation of EGFR inhibitors, compound (2) was selected as a lead for optimization. (2) was identified during a previous study for the development of thieno[2,3- d ]pyrimidine-based dual EGFR/HER2 inhibitors where it demonstrated good dual EGFR/HER2 inhibition and selective anti-proliferative activity against the lapatinib-sensitive cancer cell lines. Additionally, it showed modest activity against the T790M/L858R EGFR mutant. Twelve derivatives based on (2) were designed with the aim of optimizing the enzymatic and cellular activity of (2). Those twelve derivatives were prepared and tested for their inhibitory activities against EGFR, HER2 and T790M/L858R, and for their anti-proliferative activity against the cancer cell lines A431 and MDA-MB-468, and the NCI-60 panel of human cancer cell lines. The results provide an insight into the structural features required for EGFR/HER2 inhibition, and the conclusions drawn from this study could help direct future development of EGFR inhibitors that can overcome the current resistance mechanisms. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2022
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39. Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer.
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Chiaradonna, Ferdinando, Barozzi, Iros, Miccolo, Claudia, Bucci, Gabriele, Palorini, Roberta, Fornasari, Lorenzo, Botrugno, Oronza A., Pruneri, Giancarlo, Masullo, Michele, Passafaro, Alfonso, Galimberti, Viviana E., Fantin, Valeria R., Richon, Victoria M., Pece, Salvatore, Viale, Giuseppe, Di Fiore, Pier Paolo, Draetta, Giulio, Pelicci, Pier Giuseppe, Minucci, Saverio, and Chiocca, Susanna
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HYDROXAMIC acids , *BREAST cancer treatment , *HISTONE deacetylase inhibitors , *BREAST tumor treatment , *GENETICS of breast cancer , *CANCER cells , *GENE expression , *THERAPEUTICS - Abstract
Aims: Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines. Results: We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors. Innovation: We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA. Conclusion: In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis). Antioxid. Redox Signal. 23, 15-29. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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40. Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts.
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Valente, Sergio, Rodriguez, Veronica, Mercurio, Ciro, Vianello, Paola, Saponara, Bruna, Cirilli, Roberto, Ciossani, Giuseppe, Labella, Donatella, Marrocco, Biagina, Monaldi, Daria, Ruoppolo, Giovanni, Tilset, Mats, Botrugno, Oronza A., Dessanti, Paola, Minucci, Saverio, Mattevi, Andrea, Varasi, Mario, and Mai, Antonello
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ENANTIOMERS , *TRANYLCYPROMINE , *MONOAMINE oxidase inhibitors , *ANIMAL models in research , *GENE expression - Abstract
The pure enantiomers of the N -(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a – j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a – j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to para position of tranylcypromine phenyl ring, independently from their trans or cis stereochemistry. In particular, the para -substituted 11a,b ( trans ) and 11g,h ( cis ) compounds displayed LSD1 and MAO-A inhibition at low nanomolar levels, while were less potent against MAO-B. The meta analogs 11c,d ( trans ) and 11i,j ( cis ) were in general less potent, but more efficient against MAO-A than against LSD1. In cellular assays, all the para and meta enantiomers were able to inhibit LSD1 by inducing Gfi-1b and ITGAM gene expression, with 11b , c and 11g – i giving the highest effects. Moreover, 11b and 11g,h strongly inhibited the clonogenic potential of murine promyelocytic blasts. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
41. Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: A novel class of irreversible inhibitors of histone demethylase KDM1A.
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Vianello, Paola, Botrugno, Oronza A., Cappa, Anna, Ciossani, Giuseppe, Dessanti, Paola, Mai, Antonello, Mattevi, Andrea, Meroni, Giuseppe, Minucci, Saverio, Thaler, Florian, Tortorici, Marcello, Trifiró, Paolo, Valente, Sergio, Villa, Manuela, Varasi, Mario, and Mercurio, Ciro
- Subjects
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CYCLOPROPYLAMINES , *HISTONE demethylases , *TARGETED drug delivery , *CANCER treatment , *TRANYLCYPROMINE , *CHEMICAL synthesis - Abstract
Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
42. Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia.
- Author
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Dokla, Eman M.E., Abdel-Aziz, Amal Kamal, Milik, Sandra N., McPhillie, Martin J., Minucci, Saverio, and Abouzid, Khaled A.M.
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ACUTE myeloid leukemia , *CELL death , *WESTERN immunoblotting , *PROTEIN-tyrosine kinases , *SMALL molecules , *CELL cycle - Abstract
[Display omitted] • A benzimidazole derivative with nanomolar activity against FLT3 and TrKA kinase. • 4ACP was identified via scaffold hopping & structural simplification of quizartinib. • 4ACP prompted apoptotic and necrotic cell death and G0/G1 cell cycle arrest. • 4ACP exhibited selective antiproliferative profile and low toxicity in normal cells. • 4ACP represents a novel FLT3/TrKA dual kinase inhibitor for targeted therapy of AML. FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML. Guided by ligand-based design and structure simplification of the FLT3 inhibitor, quizartinib, we developed a benzimidazole-based small molecule, 4ACP , that exhibited nanomolar activity against wild-type FLT3, FLT3-Internal tandem duplications (FLT3-ITD), and FLT3-D835Y (FLT3-TKD) mutation (IC 50 = 43.8, 97.2, and 92.5 nM respectively). Additionally, 4ACP demonstrated potent activity against colon cancer KM12 cell line (IC 50 = 358 nM) and subsequent mechanistic deconvolution identified TrKA enzyme as a second plausible target (IC 50 = 23.6 nM) for our compound. 4ACP manifested preferential antiproliferative activity against FLT3-ITD positive AML cell lines (MV4-11 IC 50 = 38.8 ± 10.7 nM and MOLM-13 IC 50 = 54.9 ± 4.1 nM), while lacking activity against FLT3-ITD negative AML cell lines. Western blot analysis confirmed 4ACP ability to downregulate ERK1/2 and mTOR signaling downstream of FLT3-ITD in AML cells. Furthermore, 4ACP prompted apoptotic and necrotic cell death and G0/G1 cell cycle arrest as indicated by cell cycle analysis. 4ACP did not show cytotoxic effects on normal BNL and H9c2 cells and demonstrated decreased activity against c-Kit enzyme, hence, indicating lower probability of synthetic lethal toxicity and a relatively safer profile. In light of these data, 4ACP represents a novel FLT3/TrKA dual kinase inhibitor for targeted therapy of AML. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
43. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.
- Author
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Ablain, Julien, Rice, Kim, Soilihi, Hassane, de Reynies, Aurélien, Minucci, Saverio, and de Thé, Hugues
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TREATMENT of acute promyelocytic leukemia , *TUMOR proteins , *RETINOIC acid receptors , *NUCLEAR receptors (Biochemistry) , *CELLULAR signal transduction , *CHIMERIC proteins - Abstract
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
44. Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer.
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Dokla, Eman M.E., Abdel-Aziz, Amal Kamal, Milik, Sandra N., Mahmoud, Amr H., Saadeldin, Mona Kamal, McPhillie, Martin J., Minucci, Saverio, and Abouzid, Khaled A.M.
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AURORA kinases , *BREAST cancer , *KINASE inhibitors , *MOLECULAR hybridization , *WESTERN immunoblotting , *CELL cycle - Abstract
[Display omitted] • Indolin-2-one derivatives, 6e and 8a showed potent activity against Aurora B kinase. • 6e and 8a induced G2/M arrest and apoptosis of MDA-MB-468. • 6e and 8a elicited minimal cytotoxicity in normal cell lines. • 8a inhibited AURKB and Histone H3 phosphorylation. • 8a is a promising selective Aurora B inhibitor targeting breast cancer. Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g , 6a , 6c - e , 7 , and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC 50 = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC 50 = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a 's ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
45. Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors.
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Thaler, Florian, Varasi, Mario, Abate, Agnese, Carenzi, Giacomo, Colombo, Andrea, Bigogno, Chiara, Boggio, Roberto, Zuffo, Roberto Dal, Rapetti, Daniela, Resconi, Anna, Regalia, Nickolas, Vultaggio, Stefania, Dondio, Giulio, Gagliardi, Stefania, Minucci, Saverio, and Mercurio, Ciro
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HISTONE deacetylase inhibitors , *BENZOXAZINES , *CANCER treatment , *HYDROXAMIC acids , *LABORATORY mice , *ORGANIC synthesis , *PIPERIDINE , *THERAPEUTICS - Abstract
Abstract: Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. [Copyright &y& Elsevier]
- Published
- 2013
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46. A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance.
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Santoro, Fabio, Botrugno, Oronza A., Dal Zuffo, Roberto, Pallavicini, Isabella, Matthews, Geoffrey M., Cluse, Leonie, Barozzi, Iros, Senese, Silvia, Fornasari, Lorenzo, Moretti, Simona, Altucci, Lucia, Giuseppe Pelicci, Pier, Chiocca, Susanna, Johnstone, Ricky W., and Minucci, Saverio
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HISTONE deacetylase , *NEOPLASTIC cell transformation , *TREATMENT of acute promyelocytic leukemia , *ONCOGENES , *CHIMERIC proteins , *CARCINOGENESIS , *PRECANCEROUS conditions , *LABORATORY mice - Abstract
Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML- RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR-expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdacl has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
47. The DNA demethylating agent decitabine activates the TRAIL pathway and induces apoptosis in acute myeloid leukemia
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Soncini, Matías, Santoro, Fabio, Gutierrez, Arantxa, Frigè, Gianmaria, Romanenghi, Mauro, Botrugno, Oronza A., Pallavicini, Isabella, Pelicci, PierGiuseppe, Di Croce, Luciano, and Minucci, Saverio
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DNA demethylation , *DECITABINE , *EPIGENETICS , *APOPTOSIS , *ACUTE myeloid leukemia , *DNA methyltransferases , *ACUTE promyelocytic leukemia - Abstract
Abstract: Although epigenetic drugs have been approved for use in selected malignancies, there is significant need for a better understanding of their mechanism of action. Here, we study the action of a clinically approved DNA-methyltransferase inhibitor – decitabine (DAC) – in acute myeloid leukemia (AML) cells. At low doses, DAC treatment induced apoptosis of NB4 Acute Promyelocytic Leukemia (APL) cells, which was associated with the activation of the extrinsic apoptotic pathway. Expression studies of the members of the Death Receptor family demonstrated that DAC induces the expression of TNF-related apoptosis-inducing ligand (TRAIL). Upregulation of TRAIL, upon DAC treatment, was associated with specific epigenetic modifications induced by DAC in the proximity of the TRAIL promoter, as demonstrated by DNA demethylation, increased DNaseI sensitivity and histone acetylation of a non-CpG island, CpG-rich region located 2kb upstream to the transcription start site. Luciferase assay experiments showed that this region behave as a DNA methylation sensitive transcriptional regulatory element. The CpG regulatory element was also found methylated in samples derived from APL patients. These findings have been confirmed in the non-APL, AML Kasumi cell line, suggesting that this regulatory mechanism may be extended to other AMLs. Our study suggests that DNA methylation is a regulatory mechanism relevant for silencing of the TRAIL apoptotic pathway in leukemic cells, and further elucidates the mechanism by which epigenetic drugs mediate their anti-leukemic effects. [Copyright &y& Elsevier]
- Published
- 2013
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48. Chromatin accessibility, p300, and histone acetylation define PML-RARα and AML1-ETO binding sites in acute myeloid leukemia.
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Saeed, Sadia, Logie, Colin, Francoijs, Kees-Jan, Frigè, Gianmaria, Romanenghi, Mauro, Nielsen, Fiona G., Raats, Lianne, Shahhoseini, Maryam, Huynen, Martijn, Altucci, Lucia, Minucci, Saverio, Martens, Joost H. A., and Stunnenberg, Hendrik G.
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CHROMATIN , *HISTONE acetylation , *ACUTE myeloid leukemia , *GENE expression , *HEMATOPOIESIS , *CELL lines , *DNA methylation - Abstract
Chromatin accessibility plays a key role in regulating cell type specific gene ex-pression during hematopoiesis but has also been suggested to be aberrantly regulated during leukemogenesis. To un-derstand the leukemogenic chromatin sig-nature, we analyzed acute promyelocytic leukemia, a subtype of leukemia charac-terized by the expression of RARa-fusion proteins, such as PML-RARα. We used nuclease accessibility sequencing in cell lines as well as patient blasts to identify accessible DNA elements and identi-fied > 100 000 accessible regions in each case. Using ChlP-seq, we Identified H2A.Z as a histone modification generally asso-ciated with these accessible regions, whereas unsupervised clustering analy-sis of other chromatin features, including DNA methylation, H2A.Zac, H3ac, H3K9me3, H3K27me3, and the regulatory factor p300, distinguished 6 distinct clus-ters of accessible sites, each with a char-acteristic functional makeup. Of these, PML-RARα binding was found specifi-cally at accessible chromatin regions characterized by p300 binding and hy-poacetylated hlstones. Identifying re-gions with a similar epigenetic make up in t(8;21) acute myeloid leukemia (AML) cells, another subtype of AMLs, revealed that these regions are occupied by the oncofusion protein AML1-ETO. Together, our results suggest that oncofusion pro-teins localize to accessible regions and that chromatin accessibility together with p300 binding and histone acetylation char-acterize AML1-ETO and PML-RARα bind-ing sites. [ABSTRACT FROM AUTHOR]
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- 2012
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49. MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks.
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Buschbeck, Lluis Morey,1, Carmen Brenner,2 Francesco Fazi,3 Raffaella Villa,1 Arantxa Gutierrez,1 Marcus, Nervi, Clara, Minucci, Saverio, Fuks, Francois, and Di Croce, Luciano
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CHROMATIN - Abstract
An abstract of the article "MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks," by Lluis Morey, Carmen Brenner, Raffaella Villa, Arantxa Gutierrez, Marcus Buschbeck, Clara Nervi, Saverio Minucci, Francois Fuks, and Francesco Fazi is presented.
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- 2008
50. Acetylation: A Novel Link between Double-Strand Break Repair and Autophagy.
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Shubassi, Ghadeer, Robert, Thomas, Vanoli, Fabio, Minucci, Saverio, and Foiani, Marco
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ACETYLATION , *HISTONE deacetylase , *DNA damage , *CANCER treatment , *ANTINEOPLASTIC agents - Abstract
Histone deacetylase (HDAC) inhibitors are clinically relevant because they are used as anticancer drugs. Recent evidence sheds light on an intriguing connection among the DNA damage response (DDR), protein acetylation, and autophagy. HDAC inhibitors have been shown to counteract key steps in the cellular response to doublestrand break formation by affecting checkpoint activation, homologous recombination-mediated repair of DNA lesions, and stability of crucial enzymes involved in resection of DNA ends. The degradation of the resection factors depends on autophagy, which plays a detrimental role when cells are in a hyperacetylated state and experience treatment with radiomimetic anticancer drugs. Future work will be required to further investigate the mechanisms underlying the link between acetylation, autophagy, and the DDR, as well as the significance of mTORC1 inhibitors, which are potent inducers of autophagy that are now used in cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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