Open Access
New formulation of a methylseleno-aspirin analog with anticancer activity towards colon cancer
(MDPI, 2020) Ruberte, Ana Carolina; González Gaitano, Gustavo; Sharma, Arun K.; Aydillo, Carlos; Encío Martínez, Ignacio; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak
Aspirin (ASA) has attracted wide interest of numerous scientists worldwide thanks to its chemopreventive and chemotherapeutic effects, particularly in colorectal cancer (CRC). Incorporation of selenium (Se) atom into ASA has greatly increased their anti-tumoral efficacy in CRC compared with the organic counterparts without the Se functionality, such as the promising antitumoral methylseleno-ASA analog (1a). Nevertheless, the efficacy of compound 1a in cancer cells is compromised due to its poor solubility and volatile nature. Thus, 1a has been formulated with native α-, β-and γ-cyclodextrin (CD), a modified β-CD (hydroxypropyl β-CD, HP-β-CD) and Pluronic F127, all of them non-toxic, biodegradable and FDA approved. Water solubility of 1a is enhanced with β-and HP-β-CDs and Pluronic F127. Compound 1a forms inclusion complexes with the CDs and was incorporated in the hydrophobic core of the F127 micelles. Herein, we evaluated the cytotoxic potential of 1a, alone or formulated with β-and HP-β-CDs or Pluronic F127, against CRC cells. Remarkably, 1a formulations demonstrated more sustained antitumoral activity toward CRC cells. Hence, β-CD, HP-β-CD and Pluronic F127 might be excellent vehicles to improve pharmacological properties of organoselenium compounds with solubility issues and volatile nature.
Open Access
Influence of storage temperature and packaging on bacteria and yeast viability in a plant-based fermented food
(MDPI, 2020) Cabello Olmo, Miriam; Oneca Agurruza, María; Torre Hernández, Paloma; Díaz, Jesús Vicente; Encío Martínez, Ignacio; Barajas Vélez, Miguel Ángel; Araña Ciordia, Miriam; Ciencias de la Salud; Osasun Zientziak; Agronomía, Biotecnología y Alimentación; Agronomia, Bioteknologia eta Elikadura; Gobierno de Navarra / Nafarroako Gobernua
Optimization of food storage has become a central issue for food science and biotechnology, especially in the field of functional foods. The aim of this work was to investigate the influence of different storage strategies in a fermented food product (FFP) and further determine whether the regular storage (room temperature (RT) and standard packaging (SP)) could be refined. Eight experimental conditions (four different temperatures × two packaging) were simulated and changes in FFP’s microbial ecology (total bacteria, lactic acid bacteria (LAB), and yeasts) and physicochemical characteristics (pH and moisture content (MC)) were determined following 1, 3, 6, and 12 months. All conditions tested showed a decline in microbial content due to the effect of the temperature, 37 ◦C being the most detrimental condition, while −20 and 4 ◦C seemed to be better than RT in some parameters. Vacuum packaging (VP) only had a major effect on MC and we found that VP preserved greater MC values than SP at 3, 6, and 12 months. The correlation analysis revealed that total bacteria, LAB, and yeasts were positively associated, and also both pH and MC showed a correlation. According to our results and with the purpose to maintain the load of viable microorganisms, we observed that the best storage conditions should contemplate SP and freezing or cooling temperature during a period no longer than 3 months.
Open Access
Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: identification of a Se-indomethacin analog as a potential therapeutic for breast cancer
(Elsevier, 2022) Ramos Inza, Sandra; Encío Martínez, Ignacio; Raza, Asif; Sharma, Arun K.; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB
A total of twenty-five novel carboxylic acid, methylester, methylamide or cyano nonsteroidal anti-inflammatory drug (NSAID) derivatives incorporating Se in the chemical form of selenoester were reported. Twenty Se-NSAID analogs exhibited an increase in cytotoxic potency compared with parent NSAID scaffolds (aspirin, salicylic acid, naproxen, indomethacin and ketoprofen). Top five analogs were selected to further study their cytotoxicity in a larger panel of cancer cells and were also submitted to the DTP program of the NCI's panel of 60 cancer cell lines. Compounds 4a and 4d stood out with IC50 values below 10 μM in several cancer cells along with a selectivity index higher than 5 in breast cancer cells. Remarkably, analog 4d was found to inhibit cell growth notably in two breast cancer cell lines by inducing apoptosis, and to be metabolized to release the parent NSAID along with the Se fragment. Taken together, our results show that Se-NSAID analog 4d could be a potential chemotherapeutic drug for breast cancer.
Open Access
ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity
(Sringer, 2024-05-31) Zamora Álvarez, Irene; Gutiérrez Núñez, Mirian; Pascual, Alex; Pajares Villandiego, María Josefa; Barajas Vélez, Miguel Ángel; Perez, Lillian M.; You, Sungyong; Knudsen, Beatrice S.; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMAB; Gobierno de Navarra / Nafarroako Gobernua
Purpose: tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: we analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: the transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
Open Access
Unveiling a new selenocyanate as a multitarget candidate with anticancer, antileishmanial and antibacterial potential
(MDPI, 2022) Ramos Inza, Sandra; Henriquez-Figuereo, Andreina; Moreno, Esther; Berzosa, Melibea; Encío Martínez, Ignacio; Plano, Daniel; Sanmartín, Carmen; Ciencias de la Salud; Osasun Zientziak
Currently, cancer, leishmaniasis and bacterial infections represent a serious public health burden worldwide. Six cinnamyl and benzodioxyl derivatives incorporating selenium (Se) as selenocyanate, diselenide, or selenide were designed and synthesized through a nucleophilic substitution and/or a reduction using hydrides. Ferrocene was also incorporated by a Friedel–Crafts acylation. All the compounds were screened in vitro for their antiproliferative, antileishmanial, and antibacterial properties. Their capacity to scavenge free radicals was also assessed as a first approach to test their antioxidant activity. Benzodioxyl derivatives 2a–b showed cytotoxicity against colon (HT-29) and lung (H1299) cancer cell lines, with IC50 values below 12 µM, and were also fairly selective when tested in nonmalignant cells. Selenocyanate compounds 1–2a displayed potent antileishmanial activity in L. major and L. infantum, with IC50 values below 5 µM. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 µg/mL. Ferrocene-containing selenide 2c was also identified as a potent antileishmanial agent with radical scavenging activity. Remarkably, derivative 2a with a selenocyanate moiety was found to act as a multitarget compound with antiproliferative, leishmanicidal, and antibacterial activities. Thus, the current work showed that 2a could be an appealing scaffold to design potential therapeutic drugs for multiple pathologies.
Open Access
Transcriptional regulation of type 11 17β-hydroxysteroid dehydrogenase expression in prostate cancer cells
(Elsevier, 2011) Rotinen Díaz, Mirja Sofia; Villar Bécares, Joaquín; Celay Leoz, Ion; Serrano Mendioroz, Irantzu; Notario, Vicente; Encío Martínez, Ignacio; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Type 11 Hydroxysteroid (17-beta) dehydrogenase (HSD17B11) catalyzes the conversion of 5α-androstan-3α,17β-diol into androsterone suggesting that it may play an important role in androgen metabolism. We previously described that overexpression of C/EBPα or C/EBPβ induced HSD17B11 expression in HepG2 cells but this process was not mediated by the CCAAT boxes located within its proximal promoter region. Here, we study HSD17B11 transcriptional regulation in prostate cancer (PC) cells. Transfection experiments showed that the region −107/+18 is sufficient for promoter activity in PC cells. Mutagenesis analysis indicated that Sp1 and C/EBP binding sites found in this region are essential for promoter activity. Additional experiments demonstrated that ectopic expression of Sp1 and C/EBPα upregulated HSD17B11 expression only in PC cell lines. Through DAPA and ChIP assays, specific recruitment of Sp1 and C/EBPα to the HSD17B11 promoter was detected. These results show that HSD17B11 transcription in PC cells is regulated by Sp1 and C/EBPα.
Open Access
Morphological and biochemical characterization of a cell death process induced by E3, a new synthetic diarylsulfonilurea analogue
(Hindawi, 2001) Alonso Roldán, Marta; Miglaccio, M.; Encío Martínez, Ignacio; Asumendi, A.; Martínez Merino, Víctor; Hilario, E.; García, M.; Ciencias de la Salud; Química Aplicada; Osasun Zientziak; Kimika Aplikatua
With a view to finding new compounds with improved antitumoral activity and reduced secondary effects, our group, using theoretical structure-activity studies, has designed several analogues and derivatives of diarylsulfonilureas. These compounds have been synthesized and tested “in vitro” on a panel of human tumor cell lines and showed an antitumoral activity. In the present work, we have characterized the mechanisms involved in the cell death process induced by one of these products called E3 in a CCRF-CEM cell line.
Open Access
Organoseleno cytostatic derivatives: autophagic cell death with AMPK and JNK activation
(Elsevier Masson SAS, 2019) Garnica, Pablo; Encío Martínez, Ignacio; Plano, Daniel; Palop, Juan Antonio; Sanmartín, Carmen; Ciencias de la Salud; Osasun Zientziak
Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines. Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI50 values below 10 μM. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death. Consistent with autophagy, increased Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers.
Open Access
Seleno-warfare against cancer: decoding antitumor activity of novel acylselenoureas and se-acylisoselenoureas
(MDPI, 2024) Angulo-Elizari, Eduardo; Raza, Asif; Encío Martínez, Ignacio; Sharma, Arun K.; Sanmartín, Carmen; Plano, Daniel; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
Currently, cancer remains a global health problem. Despite the existence of several treatments, including chemotherapy, immunotherapy, and radiation therapy, the survival rate for most cancer patients, particularly those with metastasis, remains unsatisfactory. Thus, there is a continuous need to develop novel, effective therapies. In this work, 22 novel molecules containing selenium are reported, including seven Se-acylisoselenoureas synthesized from aliphatic carbodiimides as well as acylselenoureas with the same carbo- and heterocycles and aliphatic amines. After an initial screening at two doses (50 and 10 µM) in MDA-MB-231 (breast), HTB-54 (lung), DU-145 (prostate), and HCT-116 (colon) tumor cell lines, the ten most active compounds were identified. Additionally, these ten hits were also submitted to the DTP program of the NCI to study their cytotoxicity in a panel of 60 cancer cell lines. Compound 4 was identified as the most potent antiproliferative compound. The results obtained showed that compound 4 presented IC50 values lower than 10 µM in the cancer cell lines, although it was not the most selective one. Furthermore, compound 4 was found to inhibit cell growth and cause cell death by inducing apoptosis partially via ROS production. Overall, our results suggest that compound 4 could be a potential chemotherapeutic drug for different types of cancer.
Open Access
Synthesis and pharmacological screening of several aroyl and heteroaroyl selenylacetic acid derivatives as cytotoxic and antiproliferative agents
(MDPI, 2009) Sanmartín, Carmen; Plano, Daniel; Domínguez, Enrique; Font, María; Calvo, Alfonso; Prior, Celia; Encío Martínez, Ignacio; Palop, Juan Antonio; Ciencias de la Salud; Osasun Zientziak
The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH(2)-COOH or Heterar-CO-Se-CH(2)-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with alpha-bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3) and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7) and one mammary gland-derived non-malignant cell line (184B5). Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar = phenyl, 3, 5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 mu M. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 mu M. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7.