Emericellopsis maritima and Purpureocillium lilacinum Marine Fungi as a Source of Functional Fractions with Antioxidant and Antitumor Potential in Colorectal Cancer: A Preliminary Study

This work was co-financed by the 2014–2020 ERDF Operational Programme and by the Department of Economy, Knowledge, and Business of the University of the Regional Government of Andalusia (project reference: FEDER-UCA18-105749).The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/jmse11102024/s1The marine environment is a promising source of natural products with possible pharmacological applications. In this sense, marine microorganisms, especially marine fungi, can produce bioactive compounds with various therapeutic properties. Colorectal cancer (CRC) represents a major health problem worldwide, since the treatments used to date are not capable of improving patient survival; that is why natural compounds from marine fungi offer a promising alternative. This study focused on evaluating the antitumor and antioxidant activity of fractions derived from the marine fungi E. maritima and P. lilacinum in two CRC cell lines T84 and SW480. Fractions Fr-EM6, Fr-EM7, Fr-EM8 and Fr-PLMOH-3 demonstrated potent cytotoxic activity in tested CRC cell lines with no activity in the non-tumor line. In particular, the Fr-PLMOH-3 fraction from P. lilacinum showed significant antiproliferative effects on T84 and SW480 cell lines and exhibited a greater cytotoxic effect on cancer stem cells compared to tumor cells. Furthermore, the Fr-EM8 fraction from E. maritima demonstrated a strong antioxidant capacity. These findings highlight the potential of compounds of marine origin as effective and selective antitumor agents for the treatment of CRC. Further studies are needed to explore the underlying mechanisms and potential clinical applications of these bioactive fractions and compounds.014–2020 ERDF Operational ProgrammeRegional Government of Andalusia FEDER-UCA18-10574

Evaluation of Novel Doxorubicin-Loaded Magnetic Wax Nanocomposite Vehicles as Cancer Combinatorial Therapy Agents

The development of nanotechnology-based solutions for cancer at a preclinical level advances at an astounding pace. So far, clinical translation of these new developments has not been able to keep the pace due to a range of different reasons. One of them is the mismatch between in vitro and in vivo results coming from the expected difference in complexity. To overcome this problem, extensive characterisation using advanced in vitro models can lead to stronger preliminary data to face in vivo tests. Here, a comprehensive in vitro validation of a combinatorial therapy nanoformulation against solid tumours is presented. The information extracted from the different in vitro models highlights the importance of advanced 3D models to fully understand the potential of this type of complex drugs."Local specific treatment of triple-negative-breast-cancer through externally triggered target-less drug carriers" project - FCT 031142ERDF through NORTE2020Portuguese Foundation for Science and Technology UTAP-EXPL/NTec/0038/20172014-2020 INTERREG Cooperation Programme Spain-Portugal (POCTEP) 0624_2IQBIONEURO_6_

Electrospraying as a Technique for the Controlled Synthesis of Biocompatible PLGA@Ag2S and PLGA@Ag2S@SPION Nanocarriers with Drug Release Capability

This research was funded "Atraccion de Talento" fellowship from the Comunidad de Madrid, grant number 2018-T1/IND-10736; the Universidad Complutense de Madrid, grant number UCM-Santander (CT63/19-CT64/19); the Junta de Andalucia (P18-HO-3882, P20_00540, A-CTS666-UGR20-FEDER); and Instituto de Salud Carlos III (PI19/01478-FEDER). P.G. acknowledges financial support from the Spanish government (MICIU) through the Ramon y Cajal research program (RyC2019-028414-I). M.F. thanks the Comunidad Autonoma de Madrid for research project No. 2017T1/BIO-4992 ("Atraccion de Talento" Action) cofunded by Universidad Complutense de Madrid. M.F. is grateful to Instituto de Salud Carlos III (ISCIII) for project No DTS20/00109 (AES-ISCIII). M.F. and L.L.C would also like to thank Comunidad de Madrid for the predoctoral grant IND2020/BIO-17523.Ag2S nanoparticles are near-infrared (NIR) probes providing emission in a specific spectral range (~1200 nm), and superparamagnetic iron oxide nanoparticles (SPION) are colloidal systems able to respond to an external magnetic field. A disadvantage of Ag2S NPs is the attenuated luminescent properties are reduced in aqueous media and human fluids. Concerning SPION, the main drawback is the generation of undesirable clusters that reduce particle stability. Here, we fabricate biocompatible hybrid nanosystems combining Ag2S NPs and SPION by the electrospraying technique for drug delivery purposes. These nanostructures are composed of poly(lactic-co-glycolic acid) (PLGA) as the polymeric matrix in connection with both Ag2S NPs and SPIONs. Initially, we fabricate a hybrid colloidal nanosystem composed of Ag2S NPs in connection with PLGA (PLGA@Ag2S) by three different routes, showing good photoluminescent (PL) properties with relatively high average decay times. Then, we incorporate SPIONs, obtaining a PLGA polymeric matrix containing both Ag2S NPs and SPION (PLGA@Ag2S@SPION). Interestingly, in this hybrid system, the location of Ag2S NPs and SPIONs depends on the synthesis route performed during electrospraying. After a detailed characterization, we demonstrate the encapsulation and release capabilities, obtaining the kinetic release using a model chemotherapeutic drug (maslinic acid). Finally, we perform in vitro cytotoxicity assays using drug-loaded hybrid systems against several tumor cell lines.Comunidad de Madrid 2018-T1/IND-10736 IND2020/BIO-17523Universidad Complutense de Madrid CT63/19-CT64/19Junta de Andalucia P18-HO-3882 P20_00540 A-CTS666-UGR20-FEDERInstituto de Salud Carlos III European Commission PI19/01478-FEDER DTS20/00109Spanish government (MICIU) through the Ramon y Cajal research program RyC2019-028414-IComunidad de Madrid 2017T1/BIO-499

Bengamide Analogues Show A Potent Antitumor Activity against Colon Cancer Cells: A Preliminary Study

C.P.A., I.C.S. and B.G.P. thank Ministerio de Educación, Cultura y Deporte for their predoctoral fellowships (FPI and FPU programmes). The authors thank the Center of Scientific Instrumentation personnel of the University of Granada for technical assistance, and the Mass Spectrometry and NMR facilities of the University of Málaga for exact mass and NMR spectroscopic assistances, respectively.The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC.MINECO BIO2014-56092-R RTI2018-098296-BI00 CTQ2016-76311European Union (EU) BIO2014-56092-R RTI2018-098296-BI00 CTQ2016-76311 P12-CTS-1507Andalusian Government P12-CTS-1507 BIO-267 CTS-107Instituto de Salud Carlos III European Union (EU) PI19/01478Junta de Andalucia PI-0102-201

Tissue Specific Promoters in Colorectal Cancer

Colorectal carcinoma is the third most prevalent cancer in the world. In the most advanced stages, the use of chemotherapy induces a poor response and is usually accompanied by other tissue damage. Significant progress based on suicide gene therapy has demonstrated that it may potentiate the classical cytotoxic effects in colorectal cancer. The inconvenience still rests with the targeting and the specificity efficiency. The main target of gene therapy is to achieve an effective vehicle to hand over therapeutic genes safely into specific cells. One possibility is the use of tumor-specific promoters overexpressed in cancers. They could induce a specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several promoters have been assayed into direct suicide genes to cancer cells. This review discusses the current status of specific tumor-promoters and their great potential in colorectal carcinoma treatment.This research was funded by FEDER, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), and Instituto de Salud Carlos III (FIS), through projects PI11/01862 and PI11/0257

Serum nuclear magnetic resonance metabolomics analysis of human metastatic colorectal cancer: Biomarkers and pathway analysis

Junta de Andalucía, Grant/Award Numbers: 102C2000004, UAL2020-AGR-B1781, P20_01041; Gobierno de España, Grant/Award Numbers: PDC2021– 121248-I00, PLEC2021–007774; Instituto de Salud Carlos III (ISCIII), Grant/Award Number: PI19/01478; CTS-107 and FQM-376 groupsWe describe the use of nuclear magnetic resonance metabolomics to analyze blood serum samples from healthy individuals (n = 26) and those with metastatic colorectal cancer (CRC; n = 57). The assessment, employing both linear and nonlinear multivari- ate data analysis techniques, revealed specific metabolite changes associated with metastatic CRC, including increased levels of lactate, glutamate, and pyruvate, and decreased levels of certain amino acids and total fatty acids. Biomarker ratios such as glutamate-to-glutamine and pyruvate-to-alanine were also found to be related to CRC. The study also found that glutamate was linked to progression-free survival and that both glutamate and 3-hydroxybutyrate were risk factors for metastatic CRC. Additionally, gas chromatography coupled to flame-ionization detection was utilized to analyze the fatty acid profile and pathway analysis was performed on the profiled metabolites to understand the metabolic processes involved in CRC. A correlation was also found between the presence of certain metabolites in the blood of CRC patients and certain clinical features.Junta de Andalucia 102C2000004, UAL2020-AGR-B1781, P20_01041Gobierno de España MCIN/AEI/10.13039/501100011033/Unión Europea “Next GenerationEU”/PRTR (PDC2021–121248-I00 and PLEC2021–007774)Instituto de Salud Carlos III (ISCIII) (PI19/01478) (FEDER)CTS-107FQM-37

Evaluating Metabolite-Based Biomarkers for Early Diagnosis of Pancreatic Cancer: A Systematic Review

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with five-year survival rates around 10%. The only curative option remains complete surgical resection, but due to the delay in diagnosis, less than 20% of patients are eligible for surgery. Therefore, discovering diagnostic biomarkers for early detection is crucial for improving clinical outcomes. Metabolomics has become a powerful technology for biomarker discovery, and several metabolomic-based panels have been proposed for PDAC diagnosis, but these advances have not yet been translated into the clinic. Therefore, this review focused on summarizing metabolites identified for the early diagnosis of PDAC in the last five years. Bibliographic searches were performed in the PubMed, Scopus and WOS databases, using the terms “Biomarkers, Tumor”, “Pancreatic Neoplasms”, “Early Diagnosis”, “Metabolomics” and “Lipidome” (January 2018–March 2023), and resulted in the selection of fourteen original studies that compared PDAC patients with subjects with other pancreatic diseases. These investigations showed amino acid and lipid metabolic pathways as the most commonly altered, reflecting their potential for biomarker research. Furthermore, other relevant metabolites such as glucose and lactate were detected in the pancreas tissue and body fluids from PDAC patients. Our results suggest that the use of metabolomics remains a robust approach to improve the early diagnosis of PDAC. However, these studies showed heterogeneity with respect to the metabolomics techniques used and further studies will be needed to validate the clinical utility of these biomarkersB-TIC-414-UGR18 (Junta deAndalucía 2020) (FEDER

Active Biomolecules from Vegetable Extracts with Antitumoral Activity against Pancreas Cancer: A Systematic Review (2011–2021)

The emergence of resistance to pancreatic cancer (PC) current treatment requires the development of new therapeutic strategies. In this context, bioactive molecules from plant extracts have shown excellent properties to improve classical therapy against this type of tumor. This systematic review aims to collect all the in vitro studies related to the antiproliferative activity of isolated plant molecules that support their applicability in PC. A total of 620 articles published in the last 10 years were identified, although only 28 were finally included to meet the inclusion criteria. Our results reflect the most important biomolecules from natural compounds that induce cell death in PC and their essential mechanism of cell death, including apoptosis, pathways activated by the KRAS mutation and cycle cell arrest, among others. These in vitro studies provide an excellent molecule guide showing applications against PC and that should be tested in vivo and in clinical trials to determine their usefulness to reduce PC incidence and to improve the prognosis of these patients. However, natural compounds are isolated in small amounts, which prevents comprehensive drug screening, being necessary the role of organic synthesis for the total synthesis of natural compounds or for the synthesis of their simplified and bioactive analogs.GranadaUniversity INB-009Instituto de Salud Carlos IIIEuropean Commission DTS17/00081Spanish Government RTC2019-006870-1Junta de Andalucia P18-TP-1420 A-CTS-666-UGR20 B-CTS-122-UGR20Ministerio de Educacion, Ciencia y Deporte y Competitividad (Spain) FPU17/02977 Ibs. GRANAD

Synthetic Circular miR-21 Sponge as Tool for Lung Cancer Treatment

This work was funded by the CTS-107 Group. This work was also partially supported by a grant from the Instituto de Salud Carlos III (ISCIII) (project PI19/01478) (FEDER).Lung cancer is the most common cancer in the world and several miRNAs are associated with it. MiRNA sponges are presented as tools to inhibit miRNAs. We designed a system to capture miRNAs based on circular RNAs (circRNA). To demonstrate its usefulness, we chose miR-21, which is upregulated and implicated in lung cancer. We constructed a miR-21 sponge and inserted it into a vector that facilitates circular RNA production (Circ-21) to study its effect on growth, colony formation, and migration in lung cancer cell lines and multicellular tumor spheroids (MTS). Circ-21 induced a significant and time-dependent decrease in the growth of A549 and LL2 cells, but not in L132 cells. Furthermore, A549 and LL2 cells transfected with Circ-21 showed a lower number of colonies and migration than L132. Similar findings were seen in A549 and LL2 Circ-21 MTS, which showed a significant decrease in volume growth, but not in L132 Circ-21 MTS. Based on this, the miR-21 circular sponge may suppress the processes of tumorigenesis and progression. Therefore, our system based on circular sponges seems to be effective, as a tool for the capture of other miRNAs.Instituto de Salud Carlos III European Commission PI19/01478CTS-10

Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers.This investigation was funded by FEDER, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I), Instituto de Salud Carlos III (FIS) through projects Nos PI11/01862 and PI11/02571, and by the Consejería de Salud de la Junta de Andalucía through project No PI-0338. The authors wish to express their gratitude to G Ortiz Ferron (CIC, University of Granada, Spain) for his skillful assistance with cytometry experiments