Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers. Albeit its incidence does not score among the highest in cancer, PDAC prognosis is tremendously fatal. As a result of either aggressiveness or metastatic stage at diagnosis, chemotherapy constitutes the only marginally effective therapeutic approach. As gemcitabine (Gem) is still the cornerstone for PDAC management, the low response rate and the onset of resistant mechanisms claim for additional therapeutic strategies. The first synthetic orally active adiponectin receptor agonist AdipoRon (AdipoR) has recently been proposed as an anticancer agent in several tumors, including PDAC. To further address the AdipoR therapeutic potential, herein we investigated its pharmacodynamic interaction with Gem in human PDAC cell lines. Surprisingly, their simultaneous administration revealed a more effective action in contrasting PDAC cell growth and limiting clonogenic potential than single ones. Moreover, the combination AdipoR plus Gem persisted in being effective even in Gem-resistant MIA PaCa-2 cells. While a different ability in braking cell cycle progression between AdipoR and Gem supported their cooperating features in PDAC, mechanistically, PD98059-mediated p44/42 MAPK ablation hindered combination effectiveness. Taken together, our findings propose AdipoR as a suitable partner in Gem-based therapy and recognize the p44/42 MAPK pathway as potentially involved in combination outcomes

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery presents to us "the great paradox" consisting of countless potential targets constantly discovered and a small number of candidates being effective in human patients. Among these, cyclic-AMP response element-binding protein (CREB) has been proposed as proto-oncogene supporting tumor initiation, progression and metastasis. Overexpression and hyperactivation of CREB are frequently observed in cancer, whereas genetic and pharmacological CREB downregulation affects proliferation and apoptosis. Notably, the present review is designed to investigate the feasibility of targeting CREB in cancer therapy. In particular, starting with the latest CREB evidence in cancer pathophysiology, we evaluate the advancement state of CREB inhibitor design, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in leukemia cells. Moreover, an accurate analysis of strengths and weaknesses is also conducted to figure out whether CREB can actually represent a therapeutic candidate or just one of the innumerable preclinical cancer targets

The KDM inhibitor GSKJ4 triggers CREB down-regulation via a protein kinase A and proteasome dependent mechanism in human acute myeloid leukemia cells

Acute myeloid leukemia (AML) is a progressive hematopoietic-derived cancer arising from stepwise genetic mutations of the myeloid lineage. CREB is a nuclear transcription factor, which plays a key-role in the multistep process of leukemogenesis, thus emerging as an attractive potential drug target for AML treatment. Since epigenetic dysregulations, such as DNA methylation, histone modifications as well as chromatin remodelling, are a frequent occurrence in AML, an increasing and selective number of epi-drugs are emerging as encouraging therapeutic agents. Here, we demonstrate that the histone lysine demethylases (KDM) JMJD3/UTX inhibitor GSKJ4 results in both proliferation decrease and CREB protein down-regulation in AML cells. We found that GSKJ4 clearly decreases CREB protein, but not CREB mRNA levels. By cycloheximide assay we provide evidence that GSKJ4 reduces CREB protein stability; moreover, proteasome inhibition largely counteracts the GSKJ4-induced CREB down-regulation. Very interestingly, a rapid CREB phosphorylation at the Ser133 residue precedes CREB protein decrease in response to GSKJ4 treatment. In addition, PKA inhibition, but not ERK1/2 inhibition, almost completely prevents both GSKJ4-induced p-Ser133-CREB phosphorylation and CREB protein down-regulation. Overall, our study enforces the evidence regarding CREB as a potential druggable target, identifies the small epigenetic molecule GSKJ4 as an "inhibitor" of CREB, and encourages the design of future GSKJ4-based studies for the development of innovative approaches for AML therapy

Sequence and expression pattern of the Drosophila melanogaster mitochondrial porin gene: evidence of a conserved protein domain between fly and mouse

AbstractWe have recently cloned a cDNA encoding mitochondrial porin in Drosophila melanogaster and shown its chromosomal localization (Messina et al., FEBS Lett. (1996) 384, 9–13). Such cDNA was used as a probe for screening a genomic library. We thus cloned and sequenced a 4494-bp genomic region which contained the whole gene for the mitochondrial porin or VDAC. It was found that this D. melanogaster porin gene contains five exons, numbered IA (115 bp), IB (123 bp), II (320 bp), III (228 bp) and IV (752 bp). The exons II, III and IV contain the protein coding sequence and the 3′ untranslated sequence (3′-UTR). The first base in exon II precisely corresponds to the first base of the starting ATG codon. Exon IA corresponds to the 5′-UTR sequence reported in the published cDNA sequence. Exon IB corresponds to an alternative 5′-UTR sequence, demonstrated to be transcribed by 5′-RACE experiments. The exon-intron splicing borders and the length of the exon III perfectly match a homologous internal exon detected in the mouse genes. Such exon encodes a protein domain predicted by sequence transmembrane arrangement models to contain major hydrophilic loops and it is thus suspected to have a conserved distinct function. In situ hybridization experiments confirmed the localization of the genomic clone on the chromosome 2L at region 32B3-4. Together with genomic Southern blotting at various stringencies, the same experiment did not confirm the presence of a second genetic locus on D. melanogaster chromosomes. Northern blots demonstrated that the porin gene is a housekeeping one: three messages of approx. 1.2–1.6 kbp are transcribed in every fly developmental stage that was studied. They were shown to derive by an alternative usage of different promoters and polyadenylation sites

Tackling hepatocellular carcinoma with individual or combinatorial immunotherapy approaches.

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, there is a single drug approved as first-line systemic therapy in advanced unresectable HCC, providing a very limited survival benefit. In earlier stages, 5-year survival rates after surgical and loco-regional therapies are extremely variable depending on the stage of disease. Nevertheless, HCC is considered an immunogenic tumor arising in chronically inflamed livers. In such a scenario, immunotherapy strategies for HCC, in particular combinations including cancer vaccines, may represent a key therapeutic tool to improve clinical outcome in HCC patients. However, a lot of improvement is needed given the disappointing results obtained so far

Los efectos de la torrencialidad en la ciudad de Tafí Viejo

Es intención de este trabajo el análisis, reflexión y crítica acerca de la torrencialidad, una problemática recurrente y aun sin solución en Tucumán. Durante el verano 1999-2000, una vez más, la población debió resignarse a padecer la pérdida de bienes materiales, roturas de calles, cañerías dañadas y al descubierto por el socavamiento de las aguas, roturas de defensas, etc., como consecuencia de la torrencialidad, efectos que pudieron verse atenuados si se hubieran implementado acciones estratégicas y una efectiva capacidad de respuesta, especialmente por parte de los organismos oficiales y de las autoridades responsables. A causa de este proceso, los habitantes de algunas zonas urbanas y suburbanas de Tafí Viejo sufren los efectos de la torrencialidad como un "desastre" (Reboratti), por el gran impacto que ejerce en la sociedad local, provocando una desorganización de la misma.Evento también conocido bajo el nombre de "II Jornadas Platenses de Geografía"Facultad de Humanidades y Ciencias de la Educació

Control of gcm RNA stability is necessary for proper glial cell fate acquisition.

The control of RNA stability is an important post-transcriptional event. While neural development is known to require proteins that bind AU-rich elements (ARE) and affect RNA half-life, the role of specific RNA stability in this process remains elusive. In the Drosophila embryo, glial fate acquisition is triggered by glial cells missing (gcm) master gene, which is transiently expressed in all gliogenic stem cells and submitted to tight transcriptional regulation. By using in vitro and in vivo site directed mutagenesis, we have discovered that gcm RNA is unstable and that its 3'UTR confers labile properties to RNA due to the presence of an ARE motif. Moreover, we show that the gliogenic potential of Gcm transcription factor increases when ARE is abolished and demonstrate the importance of gcm RNA stability in the acquisition of the glial fate. Thus, control of a single RNA half-life is crucial for nervous system differentiation

Chlorogenic Acid Enhances Doxorubicin-Mediated Cytotoxic Effect in Osteosarcoma Cells

Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility

AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

The latest scientific knowledge has provided additional insights accountable for the worst prognosis for pancreatic ductal adenocarcinoma (PDAC). Among the causative factors, the aptitude to develop resistance towards approved medications denotes the master key for understanding the lack of improvement in PDAC survival over the years. Even though several compounds have achieved encouraging results at preclinical stage, no new adjuvant agents have reached the bedside of PDAC patients lately. The adiponectin receptor agonist AdipoRon is emerging as a promising anticancer drug in different cancer models, particularly in PDAC. Building on the existing findings, we recently reinforced its candidacy in PDAC cells, proposing AdipoRon either as a suitable partner in gemcitabine-based treatment or as an effective drug in resistant cells. Crossing the current state-of-the-art, herein we provide a critical perspective on AdipoRon to figure out whether this receptor agonist can potentially be considered a future therapeutic choice in overcoming chemotherapy-induced resistance, expressly in PDAC

Los efectos de la torrencialidad en la ciudad de Tafi Viejo

Es intención de este trabajo el análisis, reflexión y crítica acerca de la torrencialidad, una problemática recurrente y aun sin solución en Tucumán. Durante el verano 1999-2000, una vez más, la población debió resignarse a padecer la pérdida de bienes materiales, roturas de calles, cañerías dañadas y al descubierto por el socavamiento de las aguas, roturas de defensas, etc., como consecuencia de la torrencialidad, efectos que pudieron verse atenuados si se hubieran implementado acciones estratégicas y una efectiva capacidad de respuesta, especialmente por parte de los organismos oficiales y de las autoridades responsables. A causa de este proceso, los habitantes de algunas zonas urbanas y suburbanas de Tafí Viejo sufren los efectos de la torrencialidad como un "desastre" (Reboratti), por el gran impacto que ejerce en la sociedad local, provocando una desorganización de la misma