AGUEDA MERCEDES TEJERA
@ufv.es
Faculty of Experimental Sciences
Universidad Francisco de Vitoria
RESEARCH, TEACHING, or OTHER INTERESTS
General Biochemistry, Genetics and Molecular Biology, Cancer Research, Genetics, Molecular Medicine
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Marta P. Osuna-Marco, Laura I. Martín-López, Águeda M. Tejera, and Blanca López-Ibor
Frontiers Media SA
IntroductionTreatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been developed over the time to maximize survival and minimize side effects.MethodsWe performed a systematic literature search in May 2023 using PubMed. We selected all clinical trials articles and multicenter studies focusing on MB. We excluded studies focusing exclusively on infants, adults, supratentorial PNETs or refractory/relapsed tumors, studies involving different tumors or different types of PNETs without differentiating survival, studies including <10 cases of MB, solely retrospective studies and those without reference to outcome and/or side effects after a defined treatment.Results1. The main poor-prognosis factors are: metastatic disease, anaplasia, MYC amplification, age younger than 36 months and some molecular subgroups. The postoperative residual tumor size is controversial.2. MB is a collection of diseases.3. MB is a curable disease at diagnosis, but survival is scarce upon relapse.4. Children should be treated by experienced neurosurgeons and in advanced centers.5. RT is an essential treatment for MB. It should be administered craniospinal, early and without interruptions.6. Craniospinal RT dose could be lowered in some low-risk patients, but these reductions should be done with caution to avoid relapses.7. Irradiation of the tumor area instead of the entire posterior fossa is safe enough.8. Hyperfractionated RT is not superior to conventional RT9. Both photon and proton RT are effective.10. CT increases survival, especially in high-risk patients.11. There are multiple drugs effective in MB. The combination of different drugs is appropriate management.12. CT should be administered after RT.13. The specific benefit of concomitant CT to RT is unknown.14. Intensified CT with stem cell rescue has no benefit compared to standard CT regimens.15. The efficacy of intraventricular/intrathecal CT is controversial.16. We should start to think about incorporating targeted therapies in front-line treatment.17. Survivors of MB still have significant side effects.ConclusionSurvival rates of MB improved greatly from 1940-1970, but since then the improvement has been smaller. We should consider introducing targeted therapy as front-line therapy.
Marta Pilar Osuna-Marco, Mónica López-Barahona, Blanca López-Ibor, and Águeda Mercedes Tejera
Frontiers Media SA
People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.
Ana Belén Alvarez-Palomo, Jordi Requena-Osete, Raul Delgado-Morales, Victoria Moreno-Manzano, Carme Grau-Bove, Agueda M. Tejera, Manel Juan Otero, Carme Barrot, Irene Santos-Barriopedro, Alejandro Vaquero,et al.
Oxford University Press (OUP)
Abstract A key challenge for clinical application of induced pluripotent stem cells (iPSC) to accurately model and treat human pathologies depends on developing a method to generate genetically stable cells to reduce long-term risks of cell transplant therapy. Here, we hypothesized that CYCLIN D1 repairs DNA by highly efficient homologous recombination (HR) during reprogramming to iPSC that reduces genetic instability and threat of neoplastic growth. We adopted a synthetic mRNA transfection method using clinically compatible conditions with CYCLIN D1 plus base factors (OCT3/4, SOX2, KLF4, LIN28) and compared with methods that use C-MYC. We demonstrate that CYCLIN D1 made iPSC have (a) lower multitelomeric signal, (b) reduced double-strand DNA breaks, (c) correct nuclear localization of RAD51 protein expression, and (d) reduced single-nucleotide polymorphism (SNP) changes per chromosome, compared with the classical reprogramming method using C-MYC. CYCLIN D1 iPSC have reduced teratoma Ki67 cell growth kinetics and derived neural stem cells successfully engraft in a hostile spinal cord injury (SCI) microenvironment with efficient survival, differentiation. We demonstrate that CYCLIN D1 promotes double-stranded DNA damage repair predominantly through HR during cell reprogramming to efficiently produce iPSC. CYCLIN D1 reduces general cell stress associated with significantly lower SIRT1 gene expression and can rescue Sirt1 null mouse cell reprogramming. In conclusion, we show synthetic mRNA transfection of CYCLIN D1 repairs DNA during reprogramming resulting in significantly improved genetically stable footprint in human iPSC, enabling a new cell reprogramming method for more accurate and reliable generation of human iPSC for disease modeling and future clinical applications.
Miguel A. Muñoz-Lorente, Paula Martínez, Águeda Tejera, Kurt Whittemore, Ana Carolina Moisés-Silva, Fàtima Bosch, and Maria A. Blasco
Public Library of Science (PLoS)
Short and dysfunctional telomeres are sufficient to induce a persistent DNA damage response at chromosome ends, which leads to the induction of senescence and/or apoptosis and to various age-related conditions, including a group of diseases known as “telomere syndromes”, which are provoked by extremely short telomeres owing to germline mutations in telomere genes. This opens the possibility of using telomerase activation as a potential therapeutic strategy to rescue short telomeres both in telomere syndromes and in age-related diseases, in this manner maintaining tissue homeostasis and ameliorating these diseases. In the past, we generated adeno-associated viral vectors carrying the telomerase gene (AAV9-Tert) and shown their therapeutic efficacy in mouse models of cardiac infarct, aplastic anemia, and pulmonary fibrosis. Although we did not observe increased cancer incidence as a consequence of Tert overexpression in any of those models, here we set to test the safety of AAV9-mediated Tert overexpression in the context of a cancer prone mouse model, owing to expression of oncogenic K-ras. As control, we also treated mice with AAV9 vectors carrying a catalytically inactive form of Tert, known to inhibit endogenous telomerase activity. We found that overexpression of Tert does not accelerate the onset or progression of lung carcinomas, even when in the setting of a p53-null background. These findings indicate that telomerase activation by using AAV9-mediated Tert gene therapy has no detectable cancer-prone effects in the context of oncogene-induced mouse tumors.
Juan Manuel Povedano, Paula Martinez, Rosa Serrano, Águeda Tejera, Gonzalo Gómez-López, Maria Bobadilla, Juana Maria Flores, Fátima Bosch, and Maria A Blasco
eLife Sciences Publications, Ltd
Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1–3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.
Elisa Varela, Miguel A. Muñoz-Lorente, Agueda M. Tejera, Sagrario Ortega, and Maria A. Blasco
Springer Science and Business Media LLC
AbstractAlthough telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with ‘hyper-long’ telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression.
Iñaki Comino-Méndez, Águeda M. Tejera, María Currás-Freixes, Laura Remacha, Pablo Gonzalvo, Raúl Tonda, Rocío Letón, María A. Blasco, Mercedes Robledo, and Alberto Cascón
Elsevier BV
Christian Bär, Bruno Bernardes de Jesus, Rosa Serrano, Agueda Tejera, Eduard Ayuso, Veronica Jimenez, Ivan Formentini, Maria Bobadilla, Jacques Mizrahi, Alba de Martino,et al.
Springer Science and Business Media LLC
Jamie S.J. Wilson, Agueda M. Tejera, Dennis Castor, Rachel Toth, Maria A. Blasco, and John Rouse
Elsevier BV
Bruno Bernardes de Jesus, Elsa Vera, Kerstin Schneeberger, Agueda M. Tejera, Eduard Ayuso, Fatima Bosch, and Maria A. Blasco
EMBO
AbstractA major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1‐ and 2‐year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase‐treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase‐treated mice, both at 1‐year and at 2‐year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof‐of‐principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase‐based treatment, and demonstrate the feasibility of anti‐aging gene therapy.See accompanying article http://dx.doi.org/10.1002/emmm.201200246
Bruno Bernardes de Jesus, Kerstin Schneeberger, Elsa Vera, Agueda Tejera, Calvin B. Harley, and Maria A. Blasco
Wiley
SummaryHere, we show that a small‐molecule activator of telomerase (TA‐65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsufficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc+/− MEFs). Importantly, TA‐65 does not cause telomere elongation or rescue DNA damage in similarly treated telomerase‐deficient G3 Terc−/− littermate MEFs. These results indicate that TA‐65 treatment results in telomerase‐dependent elongation of short telomeres and rescue of associated DNA damage, thus demonstrating that TA‐65 mechanism of action is through the telomerase pathway. In addition, we demonstrate that TA‐65 is capable of increasing mouse telomerase reverse transcriptase levels in some mouse tissues and elongating critically short telomeres when supplemented as part of a standard diet in mice. Finally, TA‐65 dietary supplementation in female mice leads to an improvement of certain health‐span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence.
Paula Martinez, Maria Thanasoula, Ana R. Carlos, Gonzalo Gómez-López, Agueda M. Tejera, Stefan Schoeftner, Orlando Dominguez, David G. Pisano, Madalena Tarsounas, and Maria A. Blasco
Springer Science and Business Media LLC
Agueda M. Tejera, Martina Stagno d'Alcontres, Maria Thanasoula, Rosa M. Marion, Paula Martinez, Chunyan Liao, Juana M. Flores, Madalena Tarsounas, and Maria A. Blasco
Elsevier BV
Carolyn J. McNees, Agueda M. Tejera, Paula Martínez, Matilde Murga, Francisca Mulero, Oscar Fernandez-Capetillo, and Maria A. Blasco
Rockefeller University Press
Telomere shortening caused by incomplete DNA replication is balanced by telomerase-mediated telomere extension, with evidence indicating that the shortest telomeres are preferred substrates in primary cells. Critically short telomeres are detected by the cellular DNA damage response (DDR) system. In budding yeast, the important DDR kinase Tel1 (homologue of ATM [ataxia telangiectasia mutated]) is vital for telomerase recruitment to short telomeres, but mammalian ATM is dispensable for this function. We asked whether closely related ATR (ATM and Rad3 related) kinase, which is important for preventing replicative stress and chromosomal breakage at common fragile sites, might instead fulfill this role. The newly created ATR-deficient Seckel mouse strain was used to examine the function of ATR in telomerase recruitment and telomere function. Telomeres were recently found to resemble fragile sites, and we show in this study that ATR has an important role in the suppression of telomere fragility and recombination. We also find that wild-type ATR levels are important to protect short telomeres from chromosomal fusions but do not appear essential for telomerase recruitment to short telomeres in primary mouse embryonic fibroblasts from the ATR-deficient Seckel mouse model. These results reveal a previously unnoticed role for mammalian ATR in telomere protection and stability.
Paula Martínez, Maria Thanasoula, Purificación Muñoz, Chunyan Liao, Agueda Tejera, Carolyn McNees, Juana M. Flores, Oscar Fernández-Capetillo, Madalena Tarsounas, and Maria A. Blasco
Cold Spring Harbor Laboratory
The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric γ-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1Δ/ΔK5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.
Rosa M. Marion, Katerina Strati, Han Li, Agueda Tejera, Stefan Schoeftner, Sagrario Ortega, Manuel Serrano, and Maria A. Blasco
Elsevier BV
Antonia Tomás-Loba, Ignacio Flores, Pablo J. Fernández-Marcos, María L. Cayuela, Antonio Maraver, Agueda Tejera, Consuelo Borrás, Ander Matheu, Peter Klatt, Juana M. Flores,et al.
Elsevier BV
Ignacio Flores, Andres Canela, Elsa Vera, Agueda Tejera, George Cotsarelis, and María A. Blasco
Cold Spring Harbor Laboratory
Identification of adult stem cells and their location (niches) is of great relevance for regenerative medicine. However, stem cell niches are still poorly defined in most adult tissues. Here, we show that the longest telomeres are a general feature of adult stem cell compartments. Using confocal telomere quantitative fluorescence in situ hybridization (telomapping), we find gradients of telomere length within tissues, with the longest telomeres mapping to the known stem cell compartments. In mouse hair follicles, we show that cells with the longest telomeres map to the known stem cell compartments, colocalize with stem cell markers, and behave as stem cells upon treatment with mitogenic stimuli. Using K15-EGFP reporter mice, which mark hair follicle stem cells, we show that GFP-positive cells have the longest telomeres. The stem cell compartments in small intestine, testis, cornea, and brain of the mouse are also enriched in cells with the longest telomeres. This constitutes the description of a novel general property of adult stem cell compartments. Finally, we make the novel finding that telomeres shorten with age in different mouse stem cell compartments, which parallels a decline in stem cell functionality, suggesting that telomere loss may contribute to stem cell dysfunction with age.
Isabelle M. Dixon, Frédéric Lopez, Agueda M. Tejera, Jean-Pierre Estève, Maria A. Blasco, Geneviève Pratviel, and Bernard Meunier
American Chemical Society (ACS)
A cationic manganese porphyrin binds strongly and selectively to G-quadruplex DNA. This compound is the most selective G4-ligand reported to date.
C Geserick, A Tejera, E González-Suárez, P Klatt, and M A Blasco
Springer Science and Business Media LLC
Ofelia A. Olivero, Agueda M. Tejera, Juan J. Fernandez, Barbara J. Taylor, Shreyasi Das, Rao L. Divi, and Miriam C. Poirier
Oxford University Press (OUP)
Antiretroviral therapy for the human immunodeficiency virus-1 (HIV-1) typically includes two nucleoside reverse transcriptase inhibitors (NRTIs). 3'-Azido-3'-deoxythymidine (AZT, Zidovudine) plus 2'-deoxy-3'-thiacytidine (3TC, Lamivudine) is a combination that is used frequently. The NRTIs are mutagenic nucleoside analogs that become incorporated into DNA and terminate replication. We therefore hypothesized that exposure to this class of drug may alter cell cycle parameters. We used flow cytometry to examine the cell cycle in human epithelioid carcinoma (HeLa) cells exposed to AZT and 3TC alone, as well as a series of AZT/3TC dose combinations: (A) 125.0 microM AZT/12.5 microM 3TC; (B) 250.0 microM AZT/25.0 microM 3TC; and (C) 500 microM AZT/50 microM 3TC. At 24 h, at all doses, there was a good cell viability (>/=68%), and incorporation of AZT into nuclear DNA. Using flow cytometry, a dose-related increase in the percentage of cells in S phase, from 9.5% with no drug, to 36.0% with dose C, was observed in cells exposed for 24 h (P = 0.001, ANOVA). A concomitant decrease in the percentage of cells in G(1) phase, from 82.6% with no drug to 58.5% with dose C, was observed in cells exposed for 24 h (P = 0.017, ANOVA). A similar S phase arrest was seen in cells exposed to 125, 250 and 500 microM AZT alone, but there was no S phase alteration with 50 microM 3TC alone, suggesting that AZT is responsible for the accumulation of cells in S phase. To elucidate the accumulation of cells in S phase and explore the cell cycle gene expression changes induced by AZT and 3TC, we used c-DNA microarray, Cell Cycle Super Array and real-time PCR. There was a strong upregulation of the DNA damage-inducible transcript 3 (DDIT3 or GADD153) in NRTI-exposed cells. In addition, AZT induced an upregulation of cyclin D1 accompanied by a downregulation of the cyclin D1-associated inhibitors P18 and P57, and the G(1)-S check point gene P21, the net effect of which would be to foster a cell progression into S phase. Cyclin A2 was down-regulated in cells exposed to AZT, suggesting a block in S-G(2)-M progression that would also be consistent with the accumulation of cells in S phase. Overall, the study demonstrates that AZT, but not 3TC, causes an arrest of cells in S phase with a consistent alteration in the expression of several cell cycle genes.
Isabelle M. Dixon, Frédéric Lopez, Jean‐Pierre Estève, Agueda M. Tejera, María A. Blasco, Geneviève Pratviel, and Bernard Meunier
Wiley
AbstractThe capacity of G‐quadruplex ligands to stabilize four‐stranded DNA makes them able to inhibit telomerase, which is involved in tumour cell proliferation. A series of cationic metalloporphyrin derivatives was prepared by making variations on a meso‐tetrakis(4‐N‐methyl‐pyridiniumyl)porphyrin skeleton (TMPyP). The DNA binding properties of nickel(II) and manganese(III) porphyrins were studied by surface plasmon resonance, and the capacity of the nickel porphyrins to inhibit telomerase was tested in a TRAP assay. The nature of the metal influences the kinetics (the process is faster for Ni than for Mn) and the mode of interaction (stacking or external binding). The chemical alterations did not lead to increased telomerase inhibition. The best selectivity for G‐quadruplex DNA was observed for Mn‐TMPyP, which has a tenfold preference for quadruplex over duplex.
Santiago Giron, Agueda M. Tejera, Giselle V. Ripoll, Daniel E. Gomez, and Daniel F. Alonso
Wiley
AbstractBackground and ObjectivesDesmopressin (DDAVP) is a synthetic derivative of vasopressin with hemostatic and fibrinolytic properties that has been used during surgery in patients with bleeding disorders. Our aim was to investigate the effect of DDAVP on lung and lymph node metastatic cell colonization using a preclinical mouse mammary carcinoma model of subcutaneous tumor manipulation and surgical excision.MethodsFemale BALB/c mice bearing the highly aggressive F3II mammary carcinoma were subjected to repeated manipulations of primary tumors (0.5 kg/cm2 during 2 min), followed (or not) by surgical excision. DDAVP was administered intravenously 30 min before and 24 h after each manipulation or surgery, at a dose of 2 μg/kg. At the end of the experiment, mice were sacrificed and necropsied.ResultsTumor manipulation induced dissemination to the axillary nodes and increased up to 6‐fold the number of metastatic lung nodules. Perioperative treatment with DDAVP dramatically reduced regional metastasis. The incidence of lymph node involvement in manipulated animals was 12% with DDAVP and 87% without treatment (P < 0.02). Histopathological analysis of axillary nodes from DDAVP‐treated animals showed sinusal histiocytosis and no evidence of cancer cells. Metastatic lung nodules were also reduced about 65% in animals treated with DDAVP (P = 0.026).ConclusionsOur results suggest a potential clinical application of DDAVP in the management of breast cancer, as well as other aggressive solid tumors. DDAVP may be useful to reduce the risk of metastatic cell colonization both during and after surgical manipulation. J. Surg. Oncol. 2002;81:38–44. © 2002 Wiley‐Liss, Inc.
Junichi Yoshii, Hitoshi Yoshiji, Shigeki Kuriyama, Yasuhide Ikenaka, Ryuichi Noguchi, Hirotsugu Okuda, Hirohisa Tsujinoue, Toshiya Nakatani, Hideki Kishida, Dai Nakae,et al.
Wiley
Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti‐angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)‐chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu‐chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu‐deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu‐chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy. © 2001 Wiley‐Liss, Inc.
Agueda M. Tejera, Daniel F. Alonso, Daniel E. Gomez, and Ofelia A. Olivero
Springer Science and Business Media LLC