1 306 125 AKT TARGETING AS A STRATEGY TO BOOST CHEMOTHERAPY EFFICACY IN NON-SMALL CELL LUNG CANCER THROUGH METABOLISM SUPPRESSION. METABOLIC REPROGRAMMING IS A HALLMARK OF CANCER DEVELOPMENT, MEDIATED BY GENETIC AND EPIGENETIC ALTERATIONS THAT MAY BE PHARMACOLOGICALLY TARGETED. AMONG ONCOGENES, THE KINASE AKT IS COMMONLY OVEREXPRESSED IN TUMORS AND FAVORS GLYCOLYSIS, PROVIDING A RATIONALE FOR USING AKT INHIBITORS. HERE, WE ADDRESSED THE QUESTION OF WHETHER AND HOW INHIBITING AKT ACTIVITY COULD IMPROVE THERAPY OF NON-SMALL CELL LUNG CANCER (NSCLC) THAT REPRESENTS MORE THAN 80% OF ALL LUNG CANCER CASES. FIRST, WE DEMONSTRATED THAT AKT INHIBITORS INTERACTED SYNERGISTICALLY WITH MICROTUBULE-TARGETING AGENTS (MTAS) AND SPECIFICALLY IN CANCER CELL LINES, INCLUDING THOSE RESISTANT TO CHEMOTHERAPY AGENTS AND ANTI-EGFR TARGETED THERAPIES. IN VIVO, WE FURTHER REVEALED THAT THE CHRONIC ADMINISTRATION OF LOW-DOSES OF PACLITAXEL - I.E. METRONOMIC SCHEDULING - AND THE ANTI-AKT PERIFOSINE WAS THE MOST EFFICIENT AND THE BEST TOLERATED TREATMENT AGAINST NSCLC. REGARDING DRUG MECHANISM OF ACTION, PERIFOSINE POTENTIATED THE PRO-APOPTOTIC EFFECTS OF PACLITAXEL, INDEPENDENTLY OF CELL CYCLE ARREST, AND COMBINING PACLITAXEL/PERIFOSINE RESULTED IN A SUSTAINED SUPPRESSION OF GLYCOLYTIC AND MITOCHONDRIAL METABOLISM. THIS STUDY POINTS OUT THAT TARGETING CANCER CELL BIOENERGETICS MAY REPRESENT A NOVEL THERAPEUTIC AVENUE IN NSCLC, AND PROVIDES A STRONG FOUNDATION FOR FUTURE CLINICAL TRIALS OF METRONOMIC MTAS COMBINED WITH AKT INHIBITORS. 2017 2 171 47 ABROGATION OF HISTONE DEACETYLASES (HDACS) DECREASES SURVIVAL OF CHRONIC MYELOID LEUKEMIA CELLS: NEW INSIGHT INTO ATTENUATING EFFECTS OF THE PI3K/C-MYC AXIS ON PANOBINOSTAT CYTOTOXICITY. ALTHOUGH THE IDENTIFICATION OF TYROSINE KINASE INHIBITORS (TKIS) HAS CHANGED THE TREATMENT PARADIGM OF MANY CANCER TYPES INCLUDING CHRONIC MYELOID LEUKEMIA (CML), STILL ADJUSTMENT OF NEOPLASTIC CELLS TO CYTOTOXIC EFFECTS OF ANTICANCER DRUGS IS A SERIOUS CHALLENGE. IN THE AREA OF DRUG RESISTANCE, EPIGENETIC ALTERATIONS ARE AT THE CENTER OF ATTENTION AND THE PRESENT STUDY AIMED TO EVALUATE WHETHER BLOCKAGE OF EPIGENETICS MECHANISMS USING A PAN-HISTONE DEACETYLASE (HDAC) INHIBITOR INDUCES CELL DEATH IN CML-DERIVED K562 CELLS. WE FOUND THAT THE ABROGATION OF HDACS USING PANOBINOSTAT RESULTED IN A REDUCTION IN SURVIVAL OF THE K562 CELL LINE THROUGH P27-MEDIATED CELL CYCLE ARREST. NOTEWORTHY, THE RESULTS OF THE SYNERGISTIC EXPERIMENTS REVEALED THAT HDAC SUPPRESSION COULD BE RECRUITED AS A WAY TO POTENTIATE CYTOTOXICITY OF IMATINIB AND TO ENHANCE THE THERAPEUTIC EFFICACY OF CML. HERE, WE PROPOSED FOR THE FIRST TIME THAT THE INHIBITORY EFFECT OF PANOBINOSTAT WAS OVERSHADOWED, AT LEAST PARTIALLY, THROUGH THE ABERRANT ACTIVATION OF THE PHOSPHOINOSITIDE 3-KINASE (PI3K)/C-MYC AXIS. MEANWHILE, WE FOUND THAT UPON BLOCKAGE OF AUTOPHAGY AND THE PROTEASOME PATHWAY, AS THE MAIN AXIS INVOLVED IN THE ACTIVATION OF AUTOPHAGY, THE ANTI-LEUKEMIC PROPERTY OF THE HDAC INHIBITOR WAS POTENTIATED. TAKEN TOGETHER, OUR STUDY SUGGESTS THE BENEFICIAL APPLICATION OF HDAC INHIBITION IN THE TREATMENT STRATEGIES OF CML; HOWEVER, FURTHER IN VIVO STUDIES ARE NEEDED TO DETERMINE THE EFFICACY OF THIS INHIBITOR, EITHER AS A SINGLE AGENT OR IN COMBINATION WITH SMALL MOLECULE INHIBITORS OF PI3K AND/OR C-MYC IN THIS MALIGNANCY. 2021 3 3195 37 HDAC INHIBITORS AUGMENTED CELL MIGRATION AND METASTASIS THROUGH INDUCTION OF PKCS LEADING TO IDENTIFICATION OF LOW TOXICITY MODALITIES FOR COMBINATION CANCER THERAPY. PURPOSE: HISTONE DEACETYLASE INHIBITORS (HDACI) ARE ACTIVELY EXPLORED AS NEW-GENERATION EPIGENETIC DRUGS BUT HAVE LOW EFFICACY IN CANCER MONOTHERAPY. TO REVEAL NEW MECHANISM FOR COMBINATION THERAPY, WE SHOW THAT HDACI INDUCE CELL DEATH BUT SIMULTANEOUSLY ACTIVATE TUMOR-PROGRESSIVE GENES TO RUIN THERAPEUTIC EFFICACY. COMBINED TREATMENTS TO TARGET TUMORIGENESIS AND HDACI-ACTIVATED METASTASIS WITH LOW TOXIC MODALITIES COULD DEVELOP NEW STRATEGIES FOR LONG-TERM CANCER THERAPY. EXPERIMENTAL DESIGN: BECAUSE METASTASIS IS THE MAJOR CAUSE OF CANCER MORTALITY, WE MEASURED CELL MIGRATION ACTIVITY AND PROFILED METASTASIS-RELATED GENE EXPRESSIONS IN HDACI-TREATED CANCER CELLS. WE DEVELOPED LOW TOXIC COMBINATION MODALITIES TARGETING TUMORIGENESIS AND HDACI-ACTIVATED METASTASIS FOR PRECLINICAL THERAPIES IN MICE. RESULTS: WE SHOWED THAT CELL MIGRATION ACTIVITY WAS DRAMATICALLY AND DOSE DEPENDENTLY ENHANCED BY VARIOUS CLASSES OF HDACI TREATMENTS IN 13 OF 30 EXAMINED HUMAN BREAST, GASTRIC, LIVER, AND LUNG CANCER CELL LINES. TUMOR METASTASIS WAS ALSO ENHANCED IN HDACI-TREATED MICE. HDACI TREATMENTS ACTIVATED MULTIPLE PKCS AND DOWNSTREAM SUBSTRATES ALONG WITH UPREGULATED PROAPOPTOTIC P21. FOR TARGETING TUMORIGENESIS AND METASTASIS WITH IMMEDIATE CLINICAL IMPACT, WE SHOWED THAT NEW MODALITIES OF HDACI COMBINED DRUGS WITH PKC INHIBITORY AGENT, CURCUMIN OR TAMOXIFEN, NOT ONLY SUPPRESSED HDACI-ACTIVATED TUMOR PROGRESSIVE PROTEINS AND CELL MIGRATION IN VITRO BUT ALSO INHIBITED TUMOR GROWTH AND METASTASIS IN VIVO. CONCLUSION: TREATMENTS OF DIFFERENT STRUCTURAL CLASSES OF HDACI SIMULTANEOUSLY INDUCED CELL DEATH AND PROMOTED CELL MIGRATION AND METASTASIS IN MULTIPLE CANCER CELL TYPES. SUPPRESSION OF HDACI-INDUCED PKCS LEADS TO DEVELOPMENT OF LOW TOXIC AND LONG-TERM THERAPEUTIC STRATEGIES TO POTENTIALLY TREAT CANCER AS A CHRONIC DISEASE. 2012 4 2659 34 EPITHELIAL-TO-MESENCHYMAL TRANSITION IN THE CONTEXT OF EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITION IN NON-SMALL-CELL LUNG CANCER. THE IDENTIFICATION OF ONCOGENIC DRIVER MUTATIONS IN NON-SMALL-CELL LUNG CANCER (NSCLC) HAS LED TO THE DEVELOPMENT OF TARGETED DRUGS. TYROSINE KINASE INHIBITORS (TKIS) DIRECTED AGAINST THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) TARGET LUNG TUMOURS BEARING EGFR-ACTIVATING MUTATIONS. THIS NEW THERAPEUTIC STRATEGY HAS GREATLY IMPROVED TUMOUR RESPONSE RATES. HOWEVER, DRUG RESISTANCE INVARIABLY OCCURS DURING TKI-BASED TREATMENT. EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) IS ONE OF THE RESISTANCE MECHANISMS IDENTIFIED IN EGFR-MUTATED NSCLC TREATED WITH TKIS. IN THIS REVIEW WE GATHER TOGETHER THE MOST IMPORTANT FINDINGS ON THIS PHENOMENON IN RELATION TO CANCER STEM CELLS AND CANCER EPIGENETICS. WE ALSO OUTLINE THE CORRELATION BETWEEN THE EFFECTS OF STROMAL FACTORS FROM THE MICROENVIRONMENT, THE TRANSCRIPTION FACTORS ACTIVATED, THE EPIGENETIC CHANGES IN CHROMATIN, AND THE EVOLUTION OF CELLULAR BEHAVIOUR. NOTABLY, EMT HAS ALREADY BEEN SHOWN TO BE THE LINK BETWEEN BENIGN LUNG DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CARCINOGENESIS. THE VARIOUS MECHANISMS OF ACQUIRED RESISTANCE TO EGFR-TKIS ARE ALSO BRIEFLY DESCRIBED TO PROVIDE BACKGROUND INFORMATION ON EMT. OUR EXTENSIVE REVIEW OF THE SCIENTIFIC LITERATURE SERVES TO HIGHLIGHT THE CELLULAR AND MOLECULAR EVENTS THAT LEAD TO THE ONSET OF EMT IN NSCLC CELLS TREATED WITH EGFR-TKIS. FINALLY, WE PUT FORWARD A HYPOTHESIS TO EXPLAIN WHY, IN SOME CASES, EMT RATHER THAN OTHER KNOWN MECHANISMS IS INVOLVED IN RESISTANCE TO TKIS. 2018 5 3193 36 HDAC INHIBITION REGULATES OXIDATIVE STRESS IN CD4(+)THELPER CELLS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER PATIENTS VIA MITOCHONDRIAL TRANSCRIPTION FACTOR A (MTTFA) MODULATING NF-KAPPAB/HIF1ALPHA AXIS. HISTONE DEACETYLASES (HDACS) PLAY A CRUCIAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELLING CHROMATIN. ISOENZYMES OF THE HDAC FAMILY EXHIBIT ABERRANT REGULATION IN A WIDE VARIETY OF CANCERS AS WELL AS SEVERAL INFLAMMATORY LUNG DISORDERS LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). INHIBITION OF HDACS IS A POTENTIAL THERAPEUTIC STRATEGY THAT COULD BE USED TO REVERSE EPIGENETIC MODIFICATION. TRICHOSTATIN A (TSA), A POWERFUL HISTONE DEACETYLASE (HDAC) INHIBITOR, HAS ANTI-CANCER EFFECTS IN NUMEROUS CANCER TYPES. HOWEVER, IT IS NOT YET APPARENT HOW HDAC INHIBITORS AFFECT HUMAN NON-SMALL CELL LUNG CANCER CELLS (NSCLC) AND COPD. THIS STUDY AIMS TO INVESTIGATE TSA'S ROLE IN RESTORING MITOCHONDRIAL DYSFUNCTION AND ITS EFFECT ON HYPOXIA AND INFLAMMATION IN CD4(+)T CELLS OBTAINED FROM PATIENTS WITH COPD AND LUNG CANCER. AS A RESULT OF TREATMENT WITH TSA, THERE IS A REDUCTION IN THE EXPRESSION OF INFLAMMATORY CYTOKINES AND A DECREASED ENRICHMENT OF TRANSCRIPTIONAL FACTORS ASSOCIATED WITH INFLAMMATION AT VEGFA GENE LOCI. WE HAVE SEEN A SUBSTANTIAL DECREASE IN THE EXPRESSION OF NF-KAPPAB AND HIF1ALPHA, WHICH ARE THE CRITICAL MEDIATORS OF INFLAMMATION AND HYPOXIA, RESPECTIVELY. FOLLOWING TSA TREATMENT, MTTFA EXPRESSION WAS INCREASED, FACILITATING PATIENTS WITH COPD AND NSCLC IN THE RECOVERY OF THEIR DYSFUNCTIONAL MITOCHONDRIA. FURTHERMORE, WE HAVE DISCOVERED THAT TSA TREATMENT IN PATIENTS WITH COPD AND NSCLC MAY LEAD TO IMMUNOPROTECTIVE NESS BY INDUCING TH1NESS. OUR FINDING GIVES A NEW INSIGHT INTO THE EXISTING BODY OF KNOWLEDGE REGARDING TSA-BASED THERAPEUTIC METHODS AND HIGHLIGHTS THE NECESSITY OF EPIGENETIC THERAPY FOR THESE DEVASTATING LUNG DISORDERS. 2023 6 6896 28 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 7 3599 28 IMPORTANCE OF EPIGENETIC CHANGES IN CANCER ETIOLOGY, PATHOGENESIS, CLINICAL PROFILING, AND TREATMENT: WHAT CAN BE LEARNED FROM HEMATOLOGIC MALIGNANCIES? EPIGENETIC ALTERATIONS REPRESENT A KEY CANCER HALLMARK, EVEN IN HEMATOLOGIC MALIGNANCIES (HMS) OR BLOOD CANCERS, WHOSE CLINICAL FEATURES DISPLAY A HIGH INTER-INDIVIDUAL VARIABILITY. EVIDENCE ACCUMULATED IN RECENT YEARS INDICATES THAT INACTIVATING DNA HYPERMETHYLATION PREFERENTIALLY TARGETS THE SUBSET OF POLYCOMB GROUP (PCG) GENES THAT ARE REGULATORS OF DEVELOPMENTAL PROCESSES. CONVERSELY, ACTIVATING DNA HYPOMETHYLATION TARGETS ONCOGENIC SIGNALING PATHWAY GENES, BUT OUTCOMES OF BOTH EVENTS LEAD IN THE OVEREXPRESSION OF ONCOGENIC SIGNALING PATHWAYS THAT CONTRIBUTE TO THE STEM-LIKE STATE OF CANCER CELLS. ON THE BASIS OF RECENT EVIDENCE FROM POPULATION-BASED, CLINICAL AND EXPERIMENTAL STUDIES, WE HYPOTHESIZE THAT FACTORS ASSOCIATED WITH RISK FOR DEVELOPING A HM, SUCH AS METABOLIC SYNDROME AND CHRONIC INFLAMMATION, TRIGGER EPIGENETIC MECHANISMS TO INCREASE THE TRANSCRIPTIONAL EXPRESSION OF ONCOGENES AND ACTIVATE ONCOGENIC SIGNALING PATHWAYS. AMONG OTHERS, SIGNALING PATHWAYS ASSOCIATED WITH SUCH RISK FACTORS INCLUDE PRO-INFLAMMATORY NUCLEAR FACTOR KAPPAB (NF-KAPPAB), AND MITOGENIC, GROWTH, AND SURVIVAL JANUS KINASE (JAK) INTRACELLULAR NON-RECEPTOR TYROSINE KINASE-TRIGGERED PATHWAYS, WHICH INCLUDE SIGNALING PATHWAYS SUCH AS TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT), RAS GTPASES/MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS)/EXTRACELLULAR SIGNAL-RELATED KINASES (ERKS), PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR), AND BETA-CATENIN PATHWAYS. RECENT FINDINGS ON EPIGENETIC MECHANISMS AT WORK IN HMS AND THEIR IMPORTANCE IN THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES ARE HEREIN SUMMARIZED AND DISCUSSED. FURTHERMORE, THE ROLE OF EPIGENETIC PROCESSES IN THE DETERMINATION OF BIOLOGICAL IDENTITY, THE CONSEQUENCES FOR INTERINDIVIDUAL VARIABILITY IN DISEASE CLINICAL PROFILE, AND THE POTENTIAL OF EPIGENETIC DRUGS IN HMS ARE ALSO CONSIDERED. 2013 8 1621 49 DNA METHYLTRANSFERASES AS TARGETS FOR CANCER THERAPY. METHYLATION OF DNA AT 5-POSITION OF CYTOSINE, CATALYZED BY DNA METHYLTRANSFERASES, IS THE PREDOMINANT EPIGENETIC MODIFICATION IN MAMMALS. ABERRATIONS IN METHYLATION PLAY A CAUSAL ROLE IN A VARIETY OF DISEASES, INCLUDING CANCER. RECENT STUDIES HAVE ESTABLISHED THAT LIKE MUTATION, METHYLATION-MEDIATED GENE SILENCING OFTEN LEADS TO TUMORIGENESIS. PARADOXICALLY, GENOME-WIDE DNA HYPOMETHYLATION MAY ALSO PLAY A CAUSAL ROLE IN CARCINOGENESIS BY INDUCING CHROMOSOMAL INSTABILITY AND SPURIOUS GENE EXPRESSION. SINCE METHYLATION DOES NOT ALTER DNA BASE SEQUENCE, MUCH ATTENTION HAS BEEN FOCUSED RECENTLY ON DEVELOPING SMALL MOLECULE INHIBITORS OF DNA METHYLTRANSFERASES THAT CAN POTENTIALLY BE USED AS ANTICANCER AGENTS. VIDAZA (5-AZACYTIDINE), MARKETED BY PHARMION (BOULDER, CO, USA), WAS THE FIRST DNA METHYLTRANSFERASE INHIBITOR APPROVED BY THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) FOR CHEMOTHERAPY AGAINST MYELODYSPLASTIC SYNDROME (MDS), A HETEROGENEOUS BONE MARROW DISORDER. RECENTLY MGI PHARMA INC. (BLOOMINGTON, MN, USA) GOT FDA APPROVAL TO MARKET DACOGEN (5-AZA-2'-DEOXYCYTIDINE, OR DECITABINE) FOR TREATING MDS PATIENTS. THESE DRUGS WERE USED EARLIER AGAINST CERTAIN ANEMIAS TO INDUCE EXPRESSION OF FETAL GLOBIN GENES. INTEREST IN CLINICAL TRIALS OF THESE DRUGS AS ANTICANCER AGENTS HAS BEEN RENEWED ONLY RECENTLY BECAUSE OF REVERSAL OF METHYLATION-MEDIATED SILENCING OF CRITICAL GENES IN CANCER. CLINICAL TRIALS HAVE SHOWN THAT BOTH DRUGS HAVE THERAPEUTIC POTENTIAL AGAINST LEUKEMIA SUCH AS MDS, ACUTE MYELOID LEUKEMIA, CHRONIC MYELOGENOUS LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA. IN CONTRAST, THEIR EFFECTIVENESS WITH SOLID TUMORS APPEARS TO BE LESS PROMISING, WHICH CHALLENGES RESEARCHERS TO DEVELOP INHIBITORS WITH MORE EFFICACY AND LESS TOXICITY. THE MAJOR HINDRANCE OF THEIR USAGE AS ANTICANCER AGENTS IS THEIR INSTABILITY IN VIVO AS WELL AS THE TOXICITY SECONDARY TO THEIR EXCESSIVE INCORPORATION INTO DNA, WHICH CAUSES CELL CYCLE ARREST. GENE EXPRESSION PROFILING IN CANCER CELLS REVEALED THAT ANTINEOPLASTIC PROPERTY OF THESE DRUGS IS MEDIATED THROUGH BOTH METHYLATION-DEPENDENT AND -INDEPENDENT PATHWAYS. RECENTLY, WE HAVE SHOWN THAT TREATMENT OF CANCER CELLS WITH THESE CYTIDINE ANALOGUES ALSO INDUCES PROTEASOMAL DEGRADATION OF DNA METHYLTRANSFERASE 1, THE UBIQUITOUSLY EXPRESSED ENZYME UPREGULATED IN ALMOST ALL CANCER CELLS. DEVELOPMENT OF RELATED STABLE DRUGS THAT CAN FACILITATE GENE ACTIVATION IN CANCER CELLS BY ENHANCING DEGRADATION OF DNA METHYLTRANSFERASES WITHOUT BEING INCORPORATED INTO DNA WOULD BE IDEAL FOR CHEMOTHERAPY. IN THIS MONOGRAPH WE REVIEW HISTORICAL PERSPECTIVE AND RECENT ADVANCES ON THE MOLECULAR MECHANISMS OF ACTION AND CLINICAL APPLICATIONS OF THESE DNA HYPOMETHYLATING AGENTS. 2007 9 834 25 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 10 1542 27 DNA METHYLATION IN HAEMATOLOGICAL MALIGNANCIES: THE ROLE OF DECITABINE. NORMAL CELL DEVELOPMENT AND FUNCTION IS DEPENDENT UPON CONTROLLED GENE EXPRESSION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT CAN PLAY AN IMPORTANT ROLE IN THE CONTROL OF GENE EXPRESSION. DNA METHYLATION AT CYTOSINE RESIDUES IN GENE PROMOTER CPG SEQUENCES IS KNOWN TO INHIBIT GENE TRANSCRIPTION. INAPPROPRIATE INHIBITION OF THE TRANSCRIPTION OF TUMOUR SUPPRESSOR GENES, GENES THAT INHIBIT ANGIOGENESIS AND METASTASIS AND GENES INVOLVED IN DNA REPAIR BY UNCONTROLLED METHYLATION, CAN LEAD TO UNREGULATED GROWTH AND PROLIFERATION OF A CELL AND CARCINOGENESIS. PROMOTER HYPERMETHYLATION AFFECTING THE P16 GENE, RESULTING IN GENE SILENCING, HAS BEEN SHOWN TO OCCUR IN MANY HUMAN SOLID TUMOURS AND A 'HYPERMETHYLATION PROFILE' IN SOME LEUKAEMIAS HAS BEEN DEFINED. THE MOLECULAR MECHANISMS BY WHICH ABERRANT DNA METHYLATION TAKES PLACE DURING CARCINOGENESIS ARE STILL NOT CLEAR. HOWEVER, THE LARGE NUMBER OF TARGET GENES (INVOLVED IN TUMORIGENESIS) THAT ARE SILENCED BY ABERRANT METHYLATION SUGGESTS THAT INHIBITION OF THIS PROCESS MAY HAVE POTENTIAL AS CANCER THERAPY. DECITABINE (NSC-127716, DACOGEN; SUPERGEN) IS A POTENT AND SPECIFIC HYPOMETHYLATING AGENT AND AN INHIBITOR OF THE DNA METHYLTRANSFERASE ACTIVITY THAT MEDIATES DNA METHYLATION. DECITABINE HAS BEEN SHOWN TO HAVE A BROAD RANGE OF ANTINEOPLASTIC ACTIVITY IN PRECLINICAL STUDIES. THIS AGENT HAS EXHIBITED SIGNIFICANT ACTIVITY IN THE TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME, CHRONIC MYELOID LEUKAEMIA AND ACUTE MYELOID LEUKAEMIA, ALTHOUGH CLINICAL PHASE I AND II STUDIES WITH SOLID TUMOURS HAVE NOT BEEN VERY PROMISING. PHASE II AND III STUDIES ARE CURRENTLY ONGOING TO EVALUATE DECITABINE, BOTH ALONE AND IN COMBINATION, IN VARIOUS STAGES OF THESE HAEMATOLOGICAL MALIGNANCIES. 2003 11 1288 37 DECITABINE. PURPOSE OF REVIEW: DECITABINE IS A CYTOSINE ANALOGUE SYNTHESIZED IN THE 1960S THAT IS CURRENTLY ENJOYING A REVIVAL OF INTEREST PROMPTED BY THE ELUCIDATION OF DNA METHYLATION INHIBITION AS ITS MAJOR MECHANISM OF ACTION, ALONG WITH INCREASED UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN EPIGENETIC DYSREGULATION IN CANCER. THESE ADVANCES HAVE TURNED THIS AGENT FROM JUST ANOTHER CYTOSINE ANALOGUE INTO A TARGETED DRUG AIMED AT REVERSING EPIGENETIC SILENCING IN CANCER CELLS. HERE, RECENT CLINICAL AND TRANSLATIONAL STUDIES WITH DECITABINE ARE REVIEWED. RECENT FINDINGS: SCIENTISTS ARE NOW TAKING A CLOSER LOOK AT THIS DRUG AS A TARGETED AGENT, WITH PARTICULAR ATTENTION TO SCHEDULES OF ADMINISTRATION AND MECHANISMS OF IN VIVO EFFICACY. TWO PHASE II TRIALS HAVE REPORTED SUBSTANTIAL CLINICAL ACTIVITY OF DECITABINE IN THE MYELODYSPLASTIC SYNDROME AND IN CHRONIC MYELOGENOUS LEUKEMIA. THERE IS CONSIDERABLE INTEREST IN COMBINING DECITABINE WITH HISTONE DEACETYLASE INHIBITORS AND IN USING IT TO SENSITIZE CELLS TO CHEMOTHERAPY OR TO BIOLOGIC THERAPY. FINALLY, ONGOING EFFORTS ARE DECIPHERING THE IN VIVO MECHANISMS OF RESPONSES SEEN AFTER DECITABINE ADMINISTRATION. SUMMARY: DECITABINE, AN OLD DRUG, HAS NOW MADE A COMEBACK AS A TARGETED AGENT AND A PROTOTYPE FOR EPIGENETIC THERAPY IN CANCER. DOSES, SCHEDULES OF ADMINISTRATION, AND THE DEVELOPMENT OF RATIONAL COMBINATIONS INCLUDING THIS AGENT MUST ALL TAKE THIS CRITICAL MECHANISM OF ACTION INTO ACCOUNT. 2003 12 6371 32 THE ROLE OF MICRORNAS IN THE PATHOGENESIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES. MICRORNAS (MIRNAS) COMPRISE A RECENTLY DISCOVERED CLASS OF NON-CODING RNAS WITH REGULATORY FUNCTIONS IN POST-TRANSCRIPTIONAL GENE EXPRESSION CONTROL. MANY MIRNAS ARE LOCATED IN GENOMIC REGIONS THAT ARE FREQUENTLY DELETED IN CANCER, OR ARE SUBJECT TO EPIGENETIC AND TRANSCRIPTIONAL DEREGULATION IN CANCER CELLS. THE MIRNA TRANSCRIPTOME OF CANCER CELLS IS VERY DIFFERENT FROM THAT OF THEIR NORMAL CELL COUNTERPARTS. MIRNAS CAN EXHIBIT ONCOGENIC OR TUMOR SUPPRESSIVE OR EVEN BOTH PROPERTIES DEPENDING ON THE SPECIFIC TARGETS AND CELLULAR CONTEXT. IT IS BECOMING INCREASINGLY CLEAR THAT MIRNAS NOT ONLY SERVE AS USEFUL TUMOR BIOMARKERS WITH IMPLICATIONS FOR DIAGNOSIS, PROGNOSIS AND THE PREDICTION OF TREATMENT RESPONSES, BUT MAY ALSO BE USED FOR TARGETED CANCER TREATMENT AND EVEN AS THERAPEUTICS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE TUMOR SUPPRESSOR MIRNAS AND ONCOMIRS INVOLVED IN THE PATHOGENESIS OF LEUKEMIAS AND LYMPHOMAS, AND THEIR TARGET TRANSCRIPTS IN CANCER SIGNALING NETWORKS. IN PARTICULAR, WE FOCUS ON THE ROLE OF MIRNAS IN CHRONIC LYMPHOCYTIC AND ACUTE LYMPHOBLASTIC LEUKEMIA AND IN B-CELL LYMPHOMAS. IN THE SECOND PART, WE REVIEW THE VARIOUS ALTERNATIVE STRATEGIES OF TARGETING MIRNAS IN CANCER THERAPY. METHODS OF ONCOMIR ANTAGONIZATION BY ANTAGOMIRS OR LOCKED NUCLEID ACIDS ARE CONTRASTED WITH STRATEGIES THAT HARNESS THE TUMOR SUPPRESSIVE PROPERTIES OF CERTAIN MIRNAS FOR CANCER TREATMENT. PRECLINICAL PROGRESS, ALSO WITH REGARD TO DELIVERY STRATEGIES, POSSIBLE SIDE EFFECTS AND OTHER PHARMACOLOGICAL ASPECTS, IS PRESENTED ALONG WITH RESULTS FROM THE FIRST HUMAN TRIALS ASSESSING THE SAFETY AND EFFICACY OF MIRNA-TARGETING THERAPEUTICS. 2013 13 926 38 CHRONIC INFLAMMATION PATHWAY NF-KAPPAB COOPERATES WITH EPIGENETIC REPROGRAMMING TO DRIVE THE MALIGNANT PROGRESSION OF GLIOBLASTOMA. WITHOUT AN EFFECTIVE STRATEGY FOR TARGETED THERAPY, GLIOBLASTOMA IS STILL INCURABLE WITH A MEDIAN SURVIVAL OF ONLY 15 MONTHS. BOTH CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING ARE HALLMARKS OF CANCER. HOWEVER, THE MECHANISMS AND CONSEQUENCES OF THEIR COOPERATION IN GLIOBLASTOMA REMAIN UNKNOWN. HERE, WE DISCOVER THAT CHRONIC INFLAMMATION GOVERNS H3K27ME3 REPROGRAMMING IN GLIOBLASTOMA THROUGH THE CANONICAL NF-KAPPAB PATHWAY TO TARGET EZH2. BEING A CRUCIAL MEDIATOR OF CHRONIC INFLAMMATION, THE CANONICAL NF-KAPPAB SIGNALLING SPECIFICALLY DIRECTS THE EXPRESSION AND REDISTRIBUTION OF H3K27ME3 BUT NOT H3K4ME3, H3K9ME3 AND H3K36ME3. USING RNA-SEQ SCREENING TO FOCUS ON GENES ENCODING METHYLTRANSFERASES AND DEMETHYLASES OF HISTONE, WE IDENTIFY EZH2 AS A KEY METHYLTRANSFERASE TO CONTROL INFLAMMATION-TRIGGERED EPIGENETIC REPROGRAMMING IN GLIOMAGENESIS. MECHANISTICALLY, NF-KAPPAB SELECTIVELY DRIVES THE EXPRESSION OF EZH2 BY ACTIVATING ITS TRANSCRIPTION, CONSEQUENTLY RESULTING IN A GLOBAL CHANGE IN H3K27ME3 EXPRESSION AND DISTRIBUTION. FURTHERMORE, WE FIND THAT CO-ACTIVATION OF NF-KAPPAB AND EZH2 CONFERS THE POOREST CLINICAL OUTCOME, AND THAT THE RISK FOR GLIOBLASTOMA CAN BE ACCURATELY MOLECULARLY STRATIFIED BY NF-KAPPAB AND EZH2. IT IS NOTABLE THAT NF-KAPPAB CAN POTENTIALLY COOPERATE WITH EZH2 IN MORE THAN ONE WAY, AND MOST IMPORTANTLY, WE DEMONSTRATE A SYNERGISTIC EFFECT OF CANCER CELLS INDUCED BY COMBINATORY INHIBITION OF NF-KAPPAB AND EZH2, WHICH BOTH ARE FREQUENTLY OVER-ACTIVATED IN GLIOBLASTOMA. IN SUMMARY, WE UNCOVER A FUNCTIONAL COOPERATION BETWEEN CHRONIC INFLAMMATION AND EPIGENETIC REPROGRAMMING IN GLIOBLASTOMA, COMBINED TARGETING OF WHICH BY INHIBITORS GUARANTEED IN SAFETY AND AVAILABILITY FURNISHES A POTENT STRATEGY FOR EFFECTIVE TREATMENT OF THIS FATAL DISEASE. 2022 14 4284 27 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 15 5562 24 ROLE OF HISTONE DEACETYLASES IN PANCREAS: IMPLICATIONS FOR PATHOGENESIS AND THERAPY. IN THE LAST YEARS, OUR KNOWLEDGE OF THE PATHOGENESIS IN ACUTE AND CHRONIC PANCREATITIS (AP/CP) AS WELL AS IN PANCREATIC CANCEROGENESIS HAS SIGNIFICANTLY DIVERSIFIED. NEVERTHELESS, THE MEDICINAL THERAPEUTIC OPTIONS ARE STILL LIMITED AND THERAPEUTIC SUCCESS AND PATIENT OUTCOME ARE POOR. EPIGENETIC DEREGULATION OF GENE EXPRESSION IS KNOWN TO CONTRIBUTE TO DEVELOPMENT AND PROGRESSION OF AP AND CP AS WELL AS OF PANCREATIC CANCER. THEREFORE, THE SELECTIVE INHIBITION OF ABERRANTLY ACTIVE EPIGENETIC REGULATORS CAN BE AN EFFECTIVE OPTION FOR FUTURE THERAPIES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT REMOVE AN ACETYL GROUP FROM HISTONE TAILS, THEREBY CAUSING CHROMATIN COMPACTION AND REPRESSION OF TRANSCRIPTION. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE CURRENTLY AVAILABLE LITERATURE ADDRESSING THE ROLE OF HDACS IN THE PANCREAS AND IN PANCREATIC DISEASES. IN PANCREATIC CANCEROGENESIS, HDACS PLAY A ROLE IN THE IMPORTANT PROCESS OF EPITHELIAL-MESENCHYMAL-TRANSITION, UBIQUITIN-PROTEASOME PATHWAY AND, HYPOXIA-INDUCIBLE-FACTOR-1-ANGIOGENESIS. FINALLY, WE FOCUS ON HDACS AS POTENTIAL THERAPEUTIC TARGETS BY SUMMARIZING CURRENTLY AVAILABLE HISTONE DEACETYLASE INHIBITORS. 2015 16 208 24 ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) LINKING IMMUNITY, CHRONIC INFLAMMATION, AND CANCER. ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) IS CRITICALLY INVOLVED IN CLASS SWITCH RECOMBINATION AND SOMATIC HYPERMUTATION OF IG LOCI RESULTING IN DIVERSIFICATION OF ANTIBODIES REPERTOIRE AND PRODUCTION OF HIGH-AFFINITY ANTIBODIES AND AS SUCH REPRESENTS A PHYSIOLOGICAL TOOL TO INTRODUCE DNA ALTERATIONS. THESE PROCESSES TAKE PLACE WITHIN GERMINAL CENTERS OF SECONDARY LYMPHOID ORGANS. UNDER PHYSIOLOGICAL CONDITIONS, AID IS EXPRESSED PREDOMINANTLY IN ACTIVATED B LYMPHOCYTES. BECAUSE OF THE MUTAGENIC AND RECOMBINOGENIC POTENTIAL OF AID, ITS EXPRESSION AND ACTIVITY IS TIGHTLY REGULATED ON DIFFERENT LEVELS TO MINIMIZE THE RISK OF UNWANTED DNA DAMAGE. HOWEVER, CHRONIC INFLAMMATION AND, PROBABLY, COMBINATION OF OTHER NOT-YET-IDENTIFIED FACTORS ARE ABLE TO CREATE A MICROENVIRONMENT SUFFICIENT FOR TRIGGERING AN ABERRANT AID EXPRESSION IN B CELLS AND, IMPORTANTLY, IN NON-B-CELL BACKGROUND. UNDER THESE CIRCUMSTANCES, AID MAY TARGET ALSO NON-IG GENES, INCLUDING CANCER-RELATED GENES AS ONCOGENES, TUMOR SUPPRESSOR GENES, AND GENOMIC STABILITY GENES, AND MODULATE BOTH GENETIC AND EPIGENETIC INFORMATION. DESPITE ONGOING PROGRESS, THE COMPLETE UNDERSTANDING OF FUNDAMENTAL ASPECTS IS STILL LACKING AS (1) WHAT ARE THE CRUCIAL FACTORS TRIGGERING AN ABERRANT AID EXPRESSION/ACTIVITY INCLUDING THE IMPACT OF TH2-DRIVEN INFLAMMATION AND (2) TO WHAT EXTENT MAY ABERRANT AID IN HUMAN NON-B CELLS LEAD TO ABNORMAL CELL STATE ASSOCIATED WITH AN INCREASED RATE OF GENOMIC ALTERATIONS AS POINT MUTATIONS, SMALL INSERTIONS OR DELETIONS, AND/OR RECURRENT CHROMOSOMAL TRANSLOCATIONS DURING SOLID TUMOR DEVELOPMENT AND PROGRESSION. 2012 17 358 33 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 18 1103 27 COMBINED DUAL EFFECT OF MODULATION OF HUMAN NEUTROPHILS' OXIDATIVE BURST AND INHIBITION OF COLON CANCER CELLS PROLIFERATION BY HYDROXYCINNAMIC ACID DERIVATIVES. COLON CANCER IS ONE OF THE MOST INCIDENT CANCERS IN THE WESTERN WORLD. WHILE BOTH GENETIC AND EPIGENETIC FACTORS MAY CONTRIBUTE TO THE DEVELOPMENT OF COLON CANCER, IT IS KNOWN THAT CHRONIC INFLAMMATION ASSOCIATED TO EXCESSIVE PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES BY PHAGOCYTES MAY ULTIMATELY INITIATE THE MULTISTEP PROCESS OF COLON CANCER DEVELOPMENT. PHENOLIC COMPOUNDS, WHICH REVEAL ANTIOXIDANT AND ANTIPROLIFERATIVE ACTIVITIES IN COLON CANCER CELLS, CAN BE A GOOD APPROACH TO SURPASS THIS PROBLEM. IN THIS WORK, HYDROXYCINNAMIC AMIDES AND THE RESPECTIVE ACID PRECURSORS WERE TESTED IN VITRO FOR THEIR CAPACITY TO MODULATE HUMAN NEUTROPHILS' OXIDATIVE BURST AND SIMULTANEOUSLY TO INHIBIT GROWTH OF COLON CANCER CELLS. A PHENOLIC AMIDE DERIVATIVE, CAFFEIC ACID HEXYLAMIDE (CAHA) (4) WAS FOUND TO BE THE MOST ACTIVE COMPOUND IN BOTH ASSAYS, INHIBITING HUMAN NEUTROPHILS' OXIDATIVE BURST, RESTRAINING THE INFLAMMATORY PROCESS, INHIBITING GROWTH OF COLON CANCER CELLS AND TRIGGERING MITOCHONDRIAL DYSFUNCTION THAT LEADS CANCER CELLS TO APOPTOSIS. ALTOGETHER, THESE ACHIEVEMENTS CAN CONTRIBUTE TO THE UNDERSTANDING OF THE RELATIONSHIP BETWEEN ANTIOXIDANT AND ANTICANCER ACTIVITIES AND BASED ON THE STRUCTURE-ACTIVITY RELATIONSHIPS (SAR) ESTABLISHED CAN BE THE STARTING POINT TO FIND MORE EFFECTIVE PHENOLIC COMPOUNDS AS ANTICANCER AGENTS. 2016 19 2389 32 EPIGENETIC REPOLARIZATION OF T LYMPHOCYTES FROM CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS USING 5-AZA-2'-DEOXYCYTIDINE. T CELL IMMUNE DYSFUNCTION HAS AN IMPORTANT ROLE IN THE PROFOUND IMMUNE SUPPRESSION THAT CHARACTERIZES CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). IMPROPER POLARIZATION OF T CELLS HAS BEEN PROPOSED AS ONE OF THE MECHANISM INVOLVED. MOUNTING DATA IMPLICATES CHROMATIN REGULATION, NAMELY PROMOTER METHYLATION, IN THE PLASTICITY OF NAIVE HUMAN T CELLS. RECENT IN VITRO EVIDENCE INDICATES THAT THIS PLASTICITY MAY BE PHENOTYPICALLY ALTERED BY USING METHYLATION INHIBITORS WHICH ARE APPROVED FOR CLINICAL USE IN CERTAIN TYPES OF CANCER. THESE RESULTS BEG THE QUESTION: CAN THE INEFFECTIVE POLARIZATION OF T LYMPHOCYTES IN THE CONTEXT OF CLL BE EFFECTIVELY MODULATED USING METHYLATION INHIBITORS IN A SUSTAINABLE THERAPEUTIC FASHION? TO ANSWER THIS QUESTION OUR LABORATORY HAS STUDIED THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (5A2) IN HELPER AND CYTOTOXIC T LYMPHOCYTES FROM HEALTHY DONORS AND CLL PATIENTS IN WELL CHARACTERIZED MOLECULAR AND EPIGENETIC SIGNALING PATHWAYS INVOLVED IN EFFECTIVE POLARIZATION. MOREOVER, WE SOUGHT TO INVESTIGATE THE CONSEQUENCES OF METHYLATION INHIBITOR TREATMENT ON LYMPHOCYTE SURVIVAL, ACTIVATION INTENSITY, AND NAIVE CELL POLARIZATION. OUR DATA INDICATES THAT 5A2 TREATMENT CAN DEPOLARIZE TH2 CELLS TO EFFECTIVELY SECRETE INTERFERON GAMMA, SIGNAL VIA T-BET, AND ACHIEVE DEMETHYLATION OF CRITICAL TH1 SPECIFIC PROMOTERS. MOREOVER, WE DEMONSTRATE THAT 5A2 CAN FORCE TH1 POLARIZATION OF NAIVE T CELLS DESPITE A STRONG IL-4 STIMULI AND A LACK OF IL-12. IN CONCLUSION OUR DATA SEEKS TO DEFINE A MODALITY IN WHICH IMPROPER OR INEFFECTIVE T CELL POLARIZATION CAN BE ALTERED BY 5AZA AND COULD BE INCORPORATED IN FUTURE THERAPEUTIC INTERVENTIONS. 2011 20 3527 29 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL. 2007