473 research outputs found
Counteracting the effect of leukemia exosomes by antiangiogenic gold nanoparticles
FCT/MCTES - UID/Multi/04378/2019. FCT/MCTES - SFRH/BPD/124612/2016.Purpose: Progression of chronic myeloid leukemia (CML) is frequently associated with increased angiogenesis at the bone marrow mediated by exosomes. The capability of gold nanoparticles (AuNPs) functionalized with antiangiogenic peptides to hinder the formation of new blood vessels has been demonstrated in a chorioallantoic membrane (CAM) model. Methods: Exosomes of K562 CML cell line were isolated and their angiogenic effect assessed in a CAM model. AuNPs functionalized with antiangiogenic peptides were used to block the angiogenic effect of CML-derived exosomes, assessed by evaluation of expression levels of key modulators involved in angiogenic pathways - VEGFA, VEGFR1 (also known as FLT1) and IL8. Results: Exosomes isolated from K562 cells promoted the doubling of newly formed vessels associated with the increase of VEGFR1 expression. This is a concentration and timedependent effect. The AuNPs functionalized with antiangiogenic peptides were capable to block the angiogenic effect by modulating VEGFR1 associated pathway. Conclusion: Exosomes derived from blast cells are capable to trigger (neo)-angiogenesis, a key factor for the progression and spreading of cancer, in particular in CML. AuNPs functionalized with specific antiangiogenic peptides are capable to block the effect of the exosomes produced by malignant cells via modulation of the intrinsic VEGFR pathway. Together, these data highlight the potential of nanomedicine-based strategies against cancer proliferation.publishersversionpublishe
Exploring RAB11A Pathway to Hinder Chronic Myeloid Leukemia-Induced Angiogenesis In Vivo
project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.
This work is also funded by Fundação para a Ciência e Tecnologia in the scope of the project 2022.04315.PTDC.
Publisher Copyright:
© 2023 by the authors.Neoangiogenesis is generally correlated with poor prognosis, due to the promotion of cancer cell growth, invasion and metastasis. The progression of chronic myeloid leukemia (CML) is frequently associated with an increased vascular density in bone marrow. From a molecular point of view, the small GTP-binding protein Rab11a, involved in the endosomal slow recycling pathway, has been shown to play a crucial role for the neoangiogenic process at the bone marrow of CML patients, by controlling the secretion of exosomes by CML cells, and by regulating the recycling of vascular endothelial factor receptors. The angiogenic potential of exosomes secreted by the CML cell line K562 has been previously observed using the chorioallantoic membrane (CAM) model. Herein, gold nanoparticles (AuNPs) were functionalized with an anti-RAB11A oligonucleotide (AuNP@RAB11A) to downregulate RAB11A mRNA in K562 cell line which showed a 40% silencing of the mRNA after 6 h and 14% silencing of the protein after 12 h. Then, using the in vivo CAM model, these exosomes secreted by AuNP@RAB11A incubated K562 did not present the angiogenic potential of those secreted from untreated K562 cells. These results demonstrate the relevance of Rab11 for the neoangiogenesis mediated by tumor exosomes, whose deleterious effect may be counteracted via targeted silencing of these crucial genes; thus, decreasing the number of pro-tumoral exosomes at the tumor microenvironment.publishersversionpublishe
Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?
Metals have unique characteristics such as variable coordination modes, redox activity, and reactivity being indispensable for several biochemical processes in cells. Due to their reactivity, their concentration is tightly regulated inside the cells, and abnormal concentrations are associated with many disorders, such as cancer. As such metal complexes turned out to be very attractive as potential anticancer agents. The discovery of cisplatin was a crucial moment, which prompted the interest in Pt(II) and other metal complexes as potential anticancer agents. This chapter highlights the state of the art on metal complexes in cancer therapy, highlighting their uptake mechanisms, biological targets, toxicity, and drug resistance. Finally, based on the importance of selective target of cancer cells, drug delivery systems will also be discussed
Liquid biopsies in myeloid malignancies
Funding Information: This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019).Hematologic malignancies are the most common type of cancer affecting children and young adults, and encompass diseases, such as leukemia, lymphoma, and myeloma, all of which impact blood associated tissues such as the bone marrow, lymphatic system, and blood cells. Clinical diagnostics of these malignancies relies heavily on the use of bone marrow samples, which is painful, debilitating, and not free from risks for leukemia patients. Liquid biopsies are based on minimally invasive assessment of markers in the blood (and other fluids) and have the potential to improve the efficacy of diagnostic/therapeutic strategies in leukemia patients, providing a useful tool for the real time molecular profiling of patients. The most promising noninvasive biomarkers are circulating tumor cells, circulating tumor DNA, microRNAs, and exosomes. Herein, we discuss the role of assessing these circulating biomarkers for the understanding of tumor progression and metastasis, tumor progression dynamics through treatment and for follow-up.publishersversionpublishe
Hyperthermia induced by gold nanoparticles and visible light photothermy combined with chemotherapy to tackle doxorubicin sensitive and resistant colorectal tumor 3D spheroids
UIDB/04378/2020 SFRH/BPD/124612/2016Current cancer therapies are frequently ineffective and associated with severe side effects and with acquired cancer drug resistance. The development of effective therapies has been hampered by poor correlations between pre-clinical and clinical outcomes. Cancer cell-derived spheroids are three-dimensional (3D) structures that mimic layers of tumors in terms of oxygen and nutrient and drug resistance gradients. Gold nanoparticles (AuNP) are promising therapeutic agents which permit diminishing the emergence of secondary effects and increase therapeutic efficacy. In this work, 3D spheroids of Doxorubicin (Dox)-sensitive and -resistant colorectal carcinoma cell lines (HCT116 and HCT116-DoxR, respectively) were used to infer the potential of the combination of chemotherapy and Au-nanoparticle photothermy in the visible (green laser of 532 nm) to tackle drug resistance in cancer cells. Cell viability analysis of 3D tumor spheroids suggested that AuNPs induce cell death in the deeper layers of spheroids, further potentiated by laser irradiation. The penetration of Dox and earlier spheroid disaggregation is potentiated in combinatorial therapy with Dox, AuNP functionalized with polyethylene glycol (AuNP@PEG) and irradiation. The time point of Dox administration and irradiation showed to be important for spheroids destabilization. In HCT116-sensitive spheroids, pre-irradiation induced earlier disintegration of the 3D structure, while in HCT116 Dox-resistant spheroids, the loss of spheroid stability occurred almost instantly in post-irradiated spheroids, even with lower Dox concentrations. These results point towards the application of new strategies for cancer therapeutics, reducing side effects and resistance acquisition.publishersversionpublishe
Rational drug design of metal complexes for cancer therapy
Funding Information: This work was supported by the Fundação para a Ciência e a Tecnologia, IP/MCTES through national funds—UIDB/00100/2020 (CQE), LA/P/0056/2020 (IMS), UIDP/04378/2020 and UIDB/04378/2020 (UCIBIO), LA/P/0140/2020 (i4HB), and project PTDC/QUI-QIN/0146/2020. TM thanks FCT for Scientific Employment Stimulus (CEECIND) Initiative for the project CEECIND/00630/2017 (acknowledging FCT, as well as POPH and FSE-European Social Fund).publishersversionpublishe
Singularities of Pyogenic Streptococcal Biofilms – From Formation to Health Implication
Biofilms are generally defined as communities of cells involved in a self-produced extracellular matrix adhered to a surface. In biofilms, the bacteria are less sensitive to host defense mechanisms and antimicrobial agents, due to multiple strategies, that involve modulation of gene expression, controlled metabolic rate, intercellular communication, composition, and 3D architecture of the extracellular matrix. These factors play a key role in streptococci pathogenesis, contributing to therapy failure and promoting persistent infections. The species of the pyogenic group together with Streptococcus pneumoniae are the major pathogens belonging the genus Streptococcus, and its biofilm growth has been investigated, but insights in the genetic origin of biofilm formation are limited. This review summarizes pyogenic streptococci biofilms with details on constitution, formation, and virulence factors associated with formation.publishersversionpublishe
Gene Therapy in Cancer Treatment: Why Go Nano?
The proposal of gene therapy to tackle cancer development has been instrumental for the
development of novel approaches and strategies to fight this disease, but the efficacy of the proposed
strategies has still fallen short of delivering the full potential of gene therapy in the clinic. Despite the
plethora of gene modulation approaches, e.g., gene silencing, antisense therapy, RNA interference,
gene and genome editing, finding a way to efficiently deliver these effectors to the desired cell and
tissue has been a challenge. Nanomedicine has put forward several innovative platforms to overcome
this obstacle. Most of these platforms rely on the application of nanoscale structures, with particular
focus on nanoparticles. Herein, we review the current trends on the use of nanoparticles designed for
cancer gene therapy, including inorganic, organic, or biological (e.g., exosomes) variants, in clinical
development and their progress towards clinical applications.This work was supported by the Applied Molecular Biosciences Unit - UCIBIO which is financed by
national funds from FCT (UIDB/04378/2020), CRR (SFRH/BPD/124612/2016) and LRG (Inn-Indigo 00002/2015 RA
Detect)
Tackling Multidrug Resistance in Streptococci: From Novel Biotherapeutic Strategies to Nanomedicines
UID/Multi/04378/2020 SFRH/BD/118350/2016 Inn-Indigo 0002/2015 RA DetectThe pyogenic streptococci group includes pathogenic species for humans and other animals and has been associated with enduring morbidity and high mortality. The main reason for the treatment failure of streptococcal infections is the increased resistance to antibiotics. In recent years, infectious diseases caused by pyogenic streptococci resistant to multiple antibiotics have been raising with a significant impact to public health and veterinary industry. The rise of antibiotic-resistant streptococci has been associated to diverse mechanisms, such as efflux pumps and modifications of the antimicrobial target. Among streptococci, antibiotic resistance emerges from previously sensitive populations as result of horizontal gene transfer or chromosomal point mutations due to excessive use of antimicrobials. Streptococci strains are also recognized as biofilm producers. The increased resistance of biofilms to antibiotics among streptococci promote persistent infection, which comprise circa 80% of microbial infections in humans. Therefore, to overcome drug resistance, new strategies, including new antibacterial and antibiofilm agents, have been studied. Interestingly, the use of systems based on nanoparticles have been applied to tackle infection and reduce the emergence of drug resistance. Herein, we present a synopsis of mechanisms associated to drug resistance in (pyogenic) streptococci and discuss some innovative strategies as alternative to conventional antibiotics, such as bacteriocins, bacteriophage, and phage lysins, and metal nanoparticles. We shall provide focused discussion on the advantages and limitations of agents considering application, efficacy and safety in the context of impact to the host and evolution of bacterial resistance.publishersversionpublishe
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