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Biomedical subjects

Rosario Perona

Publications and source records attributed to Rosario Perona.

13 recordsLinked to original sources
PubMed2006

Long term responses with cetuximab therapy in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is responsible for most of the deaths associated with primary brain tumors. Standard treatment includes maximal surgical resection followed by chemotherapy and concomitant radiotherapy. Most patients, however, recur shortly after treatment. Second line treatment has little efficacy and the majority of patients die soon from the disease. Recent advances in molecular biology have implicated the epidermal growth factor receptor (EGFR) signaling pathways in the progression and resistance to standard therapies for GBM. This has prompted the evaluation of EGFR tyrosine- kinase inhibitors with encouraging results. Cetuximab is a monoclonal antibody targeted against the extra cellular domain of the EGFR with activity against different tumor types, either alone or in combination with chemotherapy and/or radiation therapy. Here we describe three patients with recurrent, heavily pretreated, EGFR expressing GBM who responded to treatment with single agent cetuximab.

Adult↗
PubMed2006

Molecular biology of malignant gliomas.

Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies.

Animals↗
PubMed2006

Cell signalling: growth factors and tyrosine kinase receptors.

The mitogenic signaling in mammalian cells is carried out mainly by growth factors that interact with receptors localized at the plasma membrane. Most of these receptors have a tyrosine kinase activity domain that is localized at the cytoplasmic region of the molecule. The interaction of the growth factors with the receptors, besides inducing the kinase activity of the receptor, activate signaling pathways the alter gene expression patterns and induce mitogenesis, or if deregulated are related to cancer. Among these receptors ERBB, VEGF, PDGF and IGF are attractive targets for directed therapies. ERBB receptors are frequently involved in the production of many types of cancers. Both, the over-expression of the growth factor and the receptor, besides mutations at the cytoplasmic tyrosine kinase domain contribute to constitutive signaling in human cancer. VEGF has a pivotal role in maintaining the tumor growth by facilitating growth of new blood vessels. Therefore, inhibition of tumor growth targeting of the tumor vasculature, by interfering with the activity of VEGFr is now a real alternative in combinatorial therapies. PDGF is a growth factor involved in growth of connective tissue and wound healing. Activating mutations of PDGFr have been found in gastrointestinal tumors and the autocrine signaling maintained by this receptor have been described in many tumors. Imatinib, and inhibitor of the tyrosine kinase activity of Bcr-Abl targets also the kinase of the PDGFr. Finally IGF-I an II have an important antiapoptotic and pro-mitogenic role in most tumors. Different inhibitors are now under clinical studies for the use in combination of chemotherapeutic drugs in the treatment of different tumors.

Angiogenesis Inhibitors↗
PubMed2004

Regulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol 3 kinase/Akt pathway and nuclear factor-kappaB.

Aerobic cells adjust the expression of antioxidant enzymes to maintain reactive oxygen species within tolerable levels. In addition, phosphatidylinositol 3 kinase (PI3K) and its downstream protein kinase effector Akt adapt cells to survive in the presence of oxidative stress. Here we provide evidence for an association between these two defense systems via transcriptional regulation of Cu/Zn-superoxide dismutase (Cu/Zn-SOD). PC12 pheochromocytoma cells expressing active Akt1 exhibit lower ROS levels in response to hydrogen peroxide, as determined with the superoxide-sensitive probe hydroethidine. Transfection of constitutive or 4-hydroxytamoxifen-inducible versions of Akt1 results in higher messenger RNA and protein levels of Cu/Zn-SOD. Luciferase reporter constructs, carrying different length fragments of the human sod1 gene promoter, have identified a region between -552 and -355 that is targeted by PI3K and Akt and that contains a putative site of regulation by nuclear factor-kappaB (NF-kappaB). Nerve growth factor (NGF) and Akt augment the transactivating activity and produce higher nuclear levels of p65-NF-kappaB. Electrophoretic mobility shift assays indicate that the putative NF-kappaB regulatory sequence binds p65-NF-kappaB more efficiently in nuclear extracts from these cells. A dominant-negative mutant of IkappaBalpha further demonstrates that the PI3K/Akt axis targets the sod1 promoter at the level of the newly characterized NF-kappaB site. These results illustrate a new mechanism by which the PI3K/Akt pathway protects cells against oxidative stress, involving the upregulation of Cu/Zn-SOD gene expression, and the results identify NF-kappaB as a key mediator in the regulation of this gene.

Animals↗
PubMed2004

Subcellular localization determines the protective effects of activated ERK2 against distinct apoptogenic stimuli in myeloid leukemia cells.

ERKs, mitogen-activated protein kinases, are well characterized as key mediators in the conveyance of signals that promote cell survival in cells of hemopoietic origin, a key factor in the upbringing of leukemogenesis. It is also well known that ERKs phosphorylate a wide array of substrates distributed throughout distinct cellular locations such as the nucleus, cytoplasm, and cell periphery, but the relative contribution of these compartmentalized signal components to the overall survival signal generated by activation of ERKs has yet to be established. To this end, we have utilized constitutively activated forms of ERK2, whose expression is restricted to the nucleus or to the cytoplasm, to investigate the consequences of compartmentalized activation of ERK in the survival of chronic myelogenous leukemia cells subjected to distinct apoptogenic stimuli. We show that cytoplasmic ERK2 activity protected against apoptosis caused by prolonged serum starvation, whereas ERK2 activation restricted to the nucleus antagonized apoptosis induced by the Bcr-Abl inhibitor STI571. On the other hand, neither cytoplasmic nor nuclear ERK2 activities were effective in counteracting apoptosis induced by UV light. These results demonstrate that the protective effects of ERK2 against defined apoptogenic stimuli are strictly dependent on the cellular localization where ERK activation takes place. Furthermore, we present evidence suggesting that the complex I kappa B-NF kappa B participates on ERK2-mediated survival mechanisms, in a fashion dependent on the cellular location where ERK2 is active and on the causative apoptogenic stimulus.

Apoptosis↗
PubMed2004

Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain).

Reactive Oxygen Species (ROS) result from cell metabolism as well as from extracellular processes. ROS exert some functions necessary for cell homeostasis maintenance. When produced in excess they play a role in the causation of cancer. ROS mediated lipid peroxides are of critical importance because they participate in chain reactions that amplify damage to biomolecules including DNA. DNA attack gives rise to mutations that may involve tumor suppressor genes or oncogenes, and this is an oncogenic mechanism. On the other hand, ROS production is a mechanism shared by many chemotherapeutic drugs due to their implication in apoptosis control. The ROS mediated cell responses depend on the duration and intensity of the cells exposing to the increased ROS environment. Thus the status redox is of great importance for oncogenetic process activation and it is also implicated in tumor susceptibility to specific chemotherapeutic drugs. Phospholipid Hydroperoxide Glutathione Peroxidase (PH-GPx) is an antioxidant enzyme that is able to directly reduce lipid peroxides even when they are bound to cellular membranes. This article will review the relevance of oxidative stress, particularly of lipid peroxidation, in cell response with special focus in carcinogenesis and cancer therapy that suggests PH-GPx as a potentially important enzyme involved in the control of this processes.

Antineoplastic Agents↗
PubMed2003

The antidiabetic agent sodium tungstate activates glycogen synthesis through an insulin receptor-independent pathway.

Sodium tungstate is a powerful antidiabetic agent when administered orally. In primary cultured hepatocytes, tungstate showed insulin-like actions, which led to an increase in glycogen synthesis and accumulation. However, this compound did not significantly alter the insulin receptor activation state or dephosphorylation rate in cultured cells (CHO-R) or in primary hepatocytes, in either short or long term treatments. In contrast, at low concentrations, tungstate induced a transient strong activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) after 5-10 min of treatment, in a similar way to insulin. Moreover, this compound did not significantly delay or inhibit the dephosphorylation of ERK1/2. ERK1/2 activation triggered a cascade of downstream events, which included the phosphorylation of p90rsk and glycogen synthase-kinase 3beta. Experiments with a specific inhibitor of ERK1/2 activation and kinase assays indicate that these proteins were directly involved in the stimulation of glycogen synthase and glycogen synthesis induced by tungstate without a direct involvement of protein kinase B (PKB/Akt). These results show a direct involvement of ERK1/2 in the mechanism of action of tungstate at the hepatic level.

Animals↗
PubMed2003

The immunosuppressant FK506 uncovers a positive regulatory cross-talk between the Hog1p and Gcn2p pathways.

The immunosuppressant Tacrolimus (FK506) has increased the survival rates of organ transplantation. FK506 exerts its immunosuppressive effect by inhibition of the protein phosphatase calcineurin in activated T-cells. Unfortunately, FK506 therapy is associated with undesired non-therapeutic effects involving targets other than calcineurin. To identify these targets we have addressed FK506 cellular toxicity in budding yeast. We show that FK506 increased cell sensitivity upon osmotic challenge independently of calcineurin and the FK506-binding proteins Fpr1p, -2p, -3p, and -4p. FK506 also induced strong amino acid starvation and activation of the general control (GCN) pathway. Tryptophan prototrophy or excess tryptophan overcame FK506 toxicity, showing that tryptophan deprivation mediated this effect. Mutation of the GCN3 and -4 genes partially alleviated FK506 toxicity, suggesting that activation of the GCN pathway by FK506 was also involved in osmotic tolerance. FK506 enhanced osmotic stress-dependent Hog1p kinase phosphorylation that was not accompanied by induction of a Hog1p-dependent reporter. Interestingly, deletion of the GCN2 gene suppressed FK506-dependent Hog1p hyperphosphorylation and restored Hog1p-dependent reporter activity. Conversely, deletion of the HOG1 gene impaired FK506-dependent activation of Gcn2p kinase and translation of a GCN4-LacZ reporter, highlighting functional cross-talk between the Gcn2p and Hog1p protein kinases. Taken together, these data demonstrate that both FK506-induced amino acid starvation and activation of the GCN pathway contribute to cell sensitivity to osmotic stress and reveal a positive regulatory loop between the Hog1p and Gcn2p pathways. Given the conserved nature of Gcn2p and Hog1p pathways, this mechanism of FK506 toxicity could be relevant to the non-therapeutic effects of FK506 therapy.

Calcineurin↗
PubMed2003

Molecular staging of prostatic cancer with RT-PCR assay for prostate-specific antigen in peripheral blood and lymph nodes: comparison with standard histological staging and immunohistochemical assessment of occult regional lymph node metastases.

BACKGROUND: About 30-40% of men with localized prostate cancer undergoing radical prostatectomy will have cancer recurrence. It is estimated that one third recur locally and two thirds develop distant metastases with or without local recurrence. METHODS: In the present study we investigate the detection of prostate-specific antigen (PSA) mRNA in peripheral blood samples (n=200 patients) and pelvic lymph nodes (n=154 patients) by PSA reverse transcriptase polymerase chain reaction (RT-PCR) and compare these results to standard histological and immunohistochemical staging. RESULTS: We have observed a statistically significant correlation of lymph node PSA RT-PCR with standard pathologic risk factors, such as Gleason score (p=0.011), the presence of Gleason patterns 4 or 5 (p=0.005), lymph node metastasis (p<0.001) and a nearly significant correlation with the pT category (p=0.087). 39.5% (57/145) of the pN0 patients had PSA mRNA detectable in their lymph nodes. Blood PSA RT-PCR showed no correlation with the aforementioned factors and was even inversely correlated with preoperative serum PSA and lymph node status. Immunohistochemistry did not detect unsuspected prostate micrometastases in any pN0 patient. CONCLUSIONS: Lymph node PSA RT-PCR correlates with the Gleason score and the presence of Gleason patterns 4 or 5. Further clinical follow-up and correlation of RT-PCR status with overall outcome is required to allow validation of lymph node RT-PCR as a predictor of distant disease recurrence.

Adenocarcinoma↗
PubMed2002

Cell stress and MEKK1-mediated c-Jun activation modulate NFkappaB activity and cell viability.

Chemotherapeutic agents such as cisplatin induce persistent activation of N-terminal c-Jun Kinase, which in turn mediates induction of apoptosis. By using a common MAPK Kinase, MEKK1, cisplatin also activates the survival transcription factor NFkappaB. We have found a cross-talk between c-Jun expression and NFkappaB transcriptional activation in response to cisplatin. Fibroblast derived from c-jun knock out mice are more resistant to cisplatin-induced cell death, and this survival advantage is mediated by upregulation of NFkappaB-dependent transcription and expression of MIAP3. This process can be reverted by ectopic expression of c-Jun in c-jun(-/-) fibroblasts, which decreases p65 transcriptional activity back to normal levels. Negative regulation of NFkappaB-dependent transcription by c-jun contributes to cisplatin-induced cell death, which suggests that inhibition of NFkappaB may potentiate the antineoplastic effect of conventional chemotherapeutic agents.

Animals↗
PubMed2002

Growth hormone protects against radiotherapy-induced cell death.

BACKGROUND: In vivo treatment with growth hormone reduces radiation-associated mortality. The molecular mechanisms underlying this effect are unknown. It has been described that increased sensitivity to ionising radiation can be due to defects in machinery involved in detection and/or repair of DNA double-strand breaks. OBJECTIVE: To study the mechanisms involved in growth hormone action on the increased survival in irradiated cells. MATERIALS AND METHODS: CHO-4 cells stably expressing the growth hormone receptor were used. A cell viability assay was carried out to analyse the increase in survival induced by growth hormone in irradiated cells. To investigate whether the DNA repair mechanism could be implicated in this effect we performed DNA reactivation assays using pHIV-LUC and pCMV-betagal plasmids as control. Identical studies were also conducted using the radiomimetic drug, bleomycin. RESULTS: Growth hormone protects CHO-4 cells from bleomycin- and radiation-induced cell death. In pHIV-LUC transfected cells, a time-dependent decrease in luciferase activity was observed after irradiation in the absence of growth hormone. However, cells pretreated with this hormone maintained reporter activity. When cells were transfected with irradiated pHIV-LUC plasmid, only the hormone-treated cells recovered the transcriptional activity. CONCLUSIONS: Growth hormone exerts a radioprotective effect in CHO-4 cells stably transfected with the complementary DNA for the rat growth hormone receptor. The radioprotection is triggered directly by the hormone and it is also observed with bleomycin. The increased survival in response to radiation and bleomycin treatment induced by growth hormone correlates with an enhanced ability of the cells to repair damaged DNA.

Animals↗