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Geopropolis is produced by some stingless bee species, such as Melipona fasciculata Smith, a native species from Brazil. This study aims to investigate the antioxidant and anti-inflammatory activities and cytotoxicity effects of geopropolis hydroethanolic extracts against lung (H460 and A549) and ovarian (A2780 and ES2) cancer cell lines and non-tumor (HUVEC) cell lines using chemical identification by LC/MS/MS analysis and in silico assays to determine which compounds are associated with bioactivity. The antioxidant activity of extracts and inhibitory activity against COX enzymes were assessed by in vitro assays, cytotoxicity effect was evaluated by the MTT assay, cell cycle was assessed by flow cytometry and apoptosis by Western blotting. The geopropolis extracts showed great radical scavenging potential, preferential inhibition of COX-2, decreased cancer cell viability, non-cytotoxic effects against the non-tumoral cell line, besides modulating the cell cycle and inducing cancer cell apoptosis through the activation of caspase-3 and PARP protein cleavage. The in silico study suggests that corilagin, typhaneoside, taraxerone and marsformosanone, identified by LC/MS/MS, can be associated with anti-inflammatory activity and cytotoxic effects. Thus, the current study suggests the potential of geopropolis concerning the research field of new pharmacological alternatives regarding cancer therapy.

This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation. These two compounds also affected cell migration, indicating their inhibition of HDAC6. An analysis of the antiproliferative activity of these compounds, which presented the most potent activity, showed that compound 3c induced cell cycle arrest and 3g induced apoptosis through caspase 3/7 activation. These results suggest HDAC6/8 as a potential target of future molecular therapies for cancer.

Although polychemotherapy regiments have improved clinical outcome for Burkitt's lymphoma (BL) patients, salvage treatment of patients with refractory disease remains very poor. Combined therapies protocols have been emerging to improve treatment strategies to circumvent responseless BL patients. We evaluate the cell death effect of histone deacetylase inhibitor (HDACI) combined with etoposide (VP-16) and cisplatin (CDDP) on BL cell lines.3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay was performed to assess drug toxicity. To establish the concentrations and time of incubation for the combined treatment, a kinetic analysis was performed for each drug on BL41 and Raji BL cell lines for 24, 48 and 72 h. Apoptosis was assessed by flow cytometry using Annexin V/propidium iodide (PI) and cleaved caspase 3 labeling assays. Caspase 9 activation and levels of Bcl-2 family proteins were analyzed by Western blot.The doses of NaB (1.0 mM), CDDP (1.0 and 2.5 μM), and VP-16 (0.1 and 0.3 μM) after 24 h of incubation were chosen for the evaluation of combined therapy. The apoptotic effects on BL cell lines of NaB/VP-16 and NaB/CDDP were followed by upregulation of Bim protein (P0.05), activation of caspase-3 and caspase-9, followed by Mcl-1 downregulation (P0.05). However, Bim overexpression was not correlated with Bcl-2 inhibition (P0.05) and was accompanied by increase in Bax expression (P0.05). The combination effects of NaB/VP-16 and NaB/CDDP were found to be synergistic and additive, respectively, in both the cell lines.The study provides strong evidence for the synergistic effects of the association with HDCI and chemotherapy in BL cells.

This paper describes the CELEPAR experience using ISO/IEC 12207 software life cycle processes and the Software-CMM Capability Maturity Model (Paulk et al., 1993) to improve and organize the maintenance and development processes.

Introduction: Histone Deacetylase Inhibitors (HDACis) have been actively explored as a new generation of anticancer drugs, generally known as epigenetic therapeutics and emerging as promising agents for the treatment of T-cell lymphomas. Panobinostat (Novartis Pharmaceuticals, Basel, Switzerland) is a novel cinnamic hydroxamic acid analogue HDACi that inhibits proliferation and induces apoptosis in tumor cell lines. Recent findings indicate that HDACi repress angiogenesis, a process essential for tumor metabolism and progression, through hypoxiainducible factors (HIF) which are the master regulator of cellular adaptation to hypoxia. In addition, HDACis apoptotic-effect was detected to occur through reactivation of Bim expression, a proapoptotic BH3-only family protein, which has attracted increasing attention as a target for tumor therapy. However, its effects on Burkitt's lymphoma (BL) cells are not entirely elucidated. Here we evaluate the efficacy of combined treatment of HDACi, Panobinostat, with Cisplatin (CDDP) or Etoposide (VP-16) in well characterized BL cell lines in order to analyze the molecular basis affected by the single and combined agents. Methods: Burkitt's Lymphoma cell lines Raji and Daudi were maintained in RPMI culture medium and incubated with Panobinostat 0.1nM combined with CDDP 1.0 and 2.5μM or VP-16 0.1 and 0.3 μM during 24h for Raji and 48h for Daudi cells. Apoptosis and mitochondrial membrane potential (MMP) were accessed by flow cytometry using Annexin-V/PI and DiOC6 respectively. Drug interaction was calculated by Fischel et al., 2005 method for determining combination index (R). Pro-Caspase-3, Pro-Caspase-9 and PARP cleavage was analyzed by western blotting using β-actin as loading control. Real-Time RT PCR was used to evaluate Bim and HIF-1α gene expressions. Results: Apoptosis was enhanced by the combined treatments (Panobinostat/CDDP and Panobinostat/VP-16), when compared with single treatment. The combination of Panobinostat and VP-16 induced apoptosis in 59,9% of Raji cells compared to 20,4% for Panobinostat alone and 33.3% for VP-16 0.3 μM alone resulting in synergistic R value of 0.77. Moreover, in Daudi cell line we observed an additive effects (R=1.1) of both combinations. The apoptosis effects were followed by MMP decreased levels in a dose-dependent manner and by cleavage of pro-caspase-3, pro-caspase-9 and PARP in both BL cell lines. Additionally, apoptotic profile was correlated with Bim and HIF-1α mRNA upregulation. Conclusions: These pre-clinical data suggests the potential therapeutic role of Panobinostat for the treatment of BL. In order to identify and validate possible targets and/or biomarkers for these combined treatments further studies are in progress. Financial support: Novartis FAF2301422, Associação Vencer FAF2301402, INCT para Controle do Câncer, CNPq 573806/2008-0, FAPERJ E26/170.026/2008 and Ministério da Saúde (M.S.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B44.