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Current cancer drug targets 09/2012; 12(7):741-2. · 5.13 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) recently emerged with a key role in multiple myeloma (MM) pathophysiology and are considered important regulators of MM cell growth and survival. Since miRNAs can act either as oncogenes or tumour suppressors, the potential of targeting the miRNA network arises as a novel therapeutic approach for human cancer. Potential strategies based on miRNA therapeutics basically rely on miRNA inhibition or miRNA replacement approaches and take benefit respectively from the use of antagomirs or synthetic miRNAs as well as from lipid-based nanoparticles which allow an efficient miRNA-delivery. The availability of experimental in vivo platforms which recapitulate the growth of MM cells within the specific human bone marrow microenvironment in immunocompromised mice (SCID-hu and SCID-synth-hu) provides powerful systems for development of miRNA-based therapeutics in MM. Preliminary findings on the anti-MM activity of synthetic miRNAs in such experimental models offer a proof-of-principle that miRNA therapeutics is a promising opportunity for this still incurable disease representing the rationale for a new venue of investigation in this specific field.
Current cancer drug targets 06/2012; 12(7):838-46. · 5.13 Impact Factor
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ABSTRACT: Mouse models of multiple myeloma (MM) are basic tools for translational research and play a fundamental role in the development of new therapeutics against plasma cell malignancies. All available models, including transplantable murine tumors in syngenic mice, xenografts of established human cell lines in immunocompromised mice and transgenic models that mirror specific steps of MM pathogenesis, have demonstrated some weaknesses in predicting clinical results, particularly for new drugs targeting the human bone marrow microenvironment (huBMM). The recent interest to models recapitulating the in vivo growth of primary MM cells in a human (SCID-hu) or humanized (SCID-synth-hu) host recipient has provided powerful platforms for the investigation of new compounds targeting MM and/or its huBMM. Here, we review and discuss strengths and weaknesses of the key in vivo models that are currently utilized in the MM preclinical investigation.
Current cancer drug targets 06/2012; 12(7):814-22. · 5.13 Impact Factor
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N Amodio,
M T Di Martino,
U Foresta,
E Leone,
M Lionetti,
M Leotta,
A M Gullà,
M R Pitari,
F Conforti,
M Rossi, [......],
M Fulciniti,
G Misso,
F Morabito,
M Ferrarini,
A Neri,
M Caraglia,
N C Munshi,
K C Anderson,
P Tagliaferri, P Tassone
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ABSTRACT: MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
Cell Death & Disease 01/2012; 3:e436. · 5.33 Impact Factor
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T Calimeri,
E Battista,
F Conforti,
P Neri,
M T Di Martino,
M Rossi,
U Foresta,
E Piro,
F Ferrara,
A Amorosi,
N Bahlis,
K C Anderson,
N Munshi,
P Tagliaferri,
F Causa, P Tassone
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(4):707-11. · 8.30 Impact Factor
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ABSTRACT: Bone disease (BD) is the hall-mark clinical feature of multiple myeloma (MM), accounting up to 60% of patients with bone pain at diagnosis and 60% with a pathologic fracture during the course of their disease. Experimental models, which recapitulate in vivo the human bone marrow microenvironment (HBMM) in immunodeficient mice have been recently developed as valuable tool for the study of MM pathophysiology as well as the experimental treatment of BD. At present, bisphosphonates are the mainstay treatment of MM-related BD. The growing information on the cellular and molecular bases of BD as well as the availability of novel anti-resorptive agents, such as the IgG1-anti-RANKL (AMG 161) Denosumab, are now depicting a new scenario where the treatment will be afforded by the use of different agents. Furthermore the availability of highthroughput molecular profiling approaches, including DNA microarrays and proteomics, is likely to provide new platforms for patients stratification and treatment individualization on specific targets. It is now the right time for a therapeutical approach which is rationally based on the complexity of the biopathology of MM-related BD.
Current cancer drug targets 11/2009; 9(7):854-70. · 5.13 Impact Factor
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ABSTRACT: Therapy with aminobisphosphonate (N-BPs), and zoledronic acid (ZOL) especially, has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that N-BPs exert their direct or indirect anti-tumour effects on cancer growth factor release, cancer cell adhesion, invasion and viability, cancer angiogenesis and cancer cell apoptosis. Here, we will discuss the molecular mechanisms of the antitumour effects induced by ZOL. Despite their well-established in vitro anti-tumour effects N-BPs have not clear in vivo anti-tumour activity in humans. The bases of these discrepancies will be discussed in the text with a special focus on the pharmacokinetic limits of N-BPs. Moreover, the following molecular and pharmacological strategies in order to overcome N-BPs limitations will be described: i) development of pharmacological combinations with other biological agents; ii) finding of new molecular targets of N-BPs; iii) development of new pharmacological formulations of N-BPs. Finally, a new scenario of integrated bio-medicine and pharmacology will be depicted in order to drive the optimization of anti-cancer activity of N-BPs.
Current cancer drug targets 11/2009; 9(7):791-800. · 5.13 Impact Factor
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P. Tassone,
M. C. Turco,
F. Tuccillo,
P. Bonelli,
G. Morrone,
L. Cecco,
M. Cerra,
H. Bond,
M. Di Nicola,
A. M. Gianni,
S. Venuta
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ABSTRACT: CD69 is an early activation antigen of peripheral blood lymphocytes and is constitutively expressed on a wide variety of bone marrow-derived cells. To further characterize the distribution and understand the potential biological role of the molecule in normal and malignant hematopoiesis, we used a novel high affinity anti-CD69 mAb (UN6) and analyzed hematopoietic progenitor cells together with a panel of myeloid and lymphoid malignancies. We report that mobilized peripheral blood CD34+ cells display detectable levels of CD69 and that the density of membrane expression correlates with the immature phenotype CD34bright Thy-1bright cells. Furthermore, during cytokine-induced differentiation, the expression of CD69 is moderately down-regulated. Analysis of hematopoietic malignancies revealed that CD69 expression correlates with the immature myeloid phenotype. Taken together these data suggest a role of CD69 during the early phase of hematopoiesis and in the leukemic transformation.
Tissue Antigens 12/2008; 48(1):65 - 68. · 2.59 Impact Factor
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M A Shammas,
H Koley,
R C Bertheau,
P Neri,
M Fulciniti, P Tassone,
S Blotta,
A Protopopov,
C Mitsiades,
R B Batchu,
K C Anderson,
A Chin,
S Gryaznov,
N C Munshi
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ABSTRACT: Human telomerase, the reverse transcriptase which extends the life span of a cell by adding telomeric repeats to chromosome ends, is expressed in most cancer cells but not in the majority of normal somatic cells. Inhibition of telomerase therefore holds great promise as anticancer therapy. We have synthesized a novel telomerase inhibitor GRN163L, a lipid-attached phosphoramidate oligonucleotide complementary to template region of the RNA subunit of telomerase. Here, we report that GRN163L is efficiently taken up by human myeloma cells without any need of transfection and is resistant to nucleolytic degradation. The exposure of myeloma cells to GRN163L led to an effective inhibition of telomerase activity, reduction of telomere length and apoptotic cell death after a lag period of 2-3 weeks. Mismatch control oligonucleotides had no effect on growth of myeloma cells. The in vivo efficacy of GRN163L was confirmed in two murine models of human multiple myeloma. In three independent experiments, significant reduction in tumor cell growth and better survival than control mice was observed. Furthermore, GRN163L-induced myeloma cell death could be significantly enhanced by Hsp90 inhibitor 17AAG. These data provide the preclinical rationale for clinical evaluation of GRN163L in myeloma and in combination with 17AAG.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2008; 22(7):1410-8. · 8.30 Impact Factor
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P Neri, P Tassone,
M Shammas,
H Yasui,
E Schipani,
R B Batchu,
S Blotta,
R Prabhala,
L Catley,
M Hamasaki,
T Hideshima,
D Chauhan,
G S Jacob,
D Picker,
S Venuta,
K C Anderson,
N C Munshi
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ABSTRACT: Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been previously reported, here we investigated its molecular and in vivo effects in MM. Gene expression analysis of MM cells identified downregulation of genes involved in adhesion, cell-signaling, cell cycle and bone morphogenetic protein (BMP) pathways and upregulation of genes implicated in apoptosis and bone development, following Atip treatment. The pathway analysis identified integrin, TGF-beta and FGF signaling as well as Wnt/beta-catenin, IGF1 and cell-cycle regulation networks as being most modulated by Atip treatment. We further evaluated its in vivo activity in three mouse models. The subcutaneous model confirmed its in vivo activity and established its dose; the SCID-hu model using INA-6 cells, confirmed its ability to overcome the protective effects of BM milieu; and the SCID-hu model using primary MM cells reconfirmed its activity in a model closest to human disease. Finally, we observed reduced number of osteoclasts and modulation of genes related to BMP pathways. Taken together, these data demonstrate the in vitro and in vivo antitumor activity of Atip, delineate potential molecular targets triggered by this agent, and provide a preclinical rational for its clinical evaluation in MM.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2008; 21(12):2519-26. · 8.30 Impact Factor
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Annals of Oncology 06/2007; 18(5):959-60. · 6.43 Impact Factor
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ABSTRACT: The design of novel therapeutic strategies based on tumour molecular features and specific carcinogenetic pathways is a compelling issue. Tumours arising in BRCA1-defective individual carriers constitute a specific entity which resembles the basal-like molecular phenotype for breast tumours, while BRCA1-defective ovarian cancer has a molecular signature which is also shared by a substantial amount of sporadic tumours. Several important issues are derived from the role of BRCA1 gene product in critical cell functions like DNA repair, transcription regulation and cell cycle checkpoint control. It has been recently demonstrated that the loss of such functions in BRCA1-defective tumours results in a specific profile of sensitivity to anti-cancer drugs. Moreover, BRCA1 appears to retain a critical role in the response of cells to stress as well as to the growth promoting stimuli generated by estrogens and peptide growth factors. Therefore, it is conceivable that loss of a functional BRCA1 produces a general de-arrangement of cellular signaling which might allow the identification of specific and high priority targets and lead to individualized signal transduction-based anti-tumour approaches. We will review the most important findings related to BRCA1 effects on cellular signaling in order to depict a general scenario for selective chemopreventive and therapeutic strategies.
Current Signal Transduction Therapy 04/2007; 2(2):165-173. · 0.50 Impact Factor
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A de Laurentiis,
M Caterino,
S Orrù,
M Ruoppolo,
F Tuccillo,
M Masullo,
I Quinto,
G Scala,
P Pucci,
C Palmieri, P Tassone,
F Salvatore,
S Venuta
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ABSTRACT: UN1 is a membrane glycoprotein that is expressed in immature human thymocytes, a subpopulation of peripheral T lymphocytes, the HPB acute lymphoblastic leukemia (ALL) T-cell line and fetal thymus. We previously reported the isolation of a monoclonal antibody (UN1 mAb) recognizing the UN1 protein that was classified as "unclustered" at the 5th and 6th International Workshop and Conference on Human Leukocyte Differentiation Antigens. UN1 was highly expressed in breast cancer tissues and was undetected in non-proliferative lesions and in normal breast tissues, indicating a role for UN1 in the development of a tumorigenic phenotype of breast cancer cells. In this study, we report a partial purification of the UN1 protein from HPB-ALL T cells by anion-exchange chromatography followed by immunoprecipitation with the UN1 mAb and MALDI-TOF MS analysis. This analysis should assist in identifying the amino acid sequence of UN1.
International Journal of Biological Macromolecules 09/2006; 39(1-3):122-6. · 2.45 Impact Factor
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ABSTRACT: Target-based therapy has been a promising anti-cancer strategy in the preclinical setting, but its efficacy is still limited in clinical practice. The latter was probably due to the lack of identification of molecular targets in order to predict clinical response and for the existence of multiple survival compensatory downstream pathways. Therefore, the use of downstream targets could be useful in order to avoid these overcoming pathways. One of these targets is Raf-kinase. In this review we describe the structure and functions of the components of Raf-kinase family and their relevance in proliferation and survival of tumor cells. Moreover, we illustrate the signal transduction pathways regulated by Raf-kinases. The main preclinical and clinical results obtained with the use of the Raf-kinase inhibitor BAY 43-9006 or sorafenib are also described. The multi-target function of sorafenib is also explained and the disclosure of new therapeutic opportunities based on the dual inhibition of cancer proliferation and neo-angiogenesis is discussed. In conclusion, Raf-kinase appears an appealing therapeutic target, even it other preclinical and clinical studies are warranted in order to evaluate the activity of sorafenib both in monotherapy and in combination with other agents.
Annals of Oncology 07/2006; 17 Suppl 7:vii124-7. · 6.43 Impact Factor
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ABSTRACT: Cellular receptors for the Epidermal Growth Factor are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors have been developed and have undergone extensive evaluation in preclinical and clinical studies. Most of these studies have been conceived on the general idea that epidermal growth factor receptor (EGFR) plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of antiCD20 monoclonal antibodies in lymphoproliferative disease and of anti HER2 agents in breast tumors overexpressing the targeted antigens. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interferring drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. Recent evidence of major responses to the EGFR inhibitor Gefitinib in tumors harboring activating mutations in the EGFR appears on line with this concept. In this article we will discuss the significance of targeting the EGFR driven survival pathways. Specifically, we will afford the point of EGFR survival signalling prioritization by means of pharmacological treatment. Finally, we will address the role of profiling technologies and of novel computational system biology-based approaches for identification of innovative strategies for effective targeting of EGFR driven survival pathways.
Current Drug Targets 06/2005; 6(3):289-300. · 3.55 Impact Factor
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ABSTRACT: The activity of NF-kappaB/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nfkappab or ikappaB genes are documented in some hematologic neoplasias, while in others dysfunction in NF-kappaB/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-kappaB/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-kappaB/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NF-kappaB/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-kappaB/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-kappaB/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-kappaB/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow.
Leukemia 02/2004; 18(1):11-7. · 9.56 Impact Factor
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P Tassone,
P Tagliaferri,
C Viscomi,
C Palmieri,
M Caraglia,
A D'Alessandro,
E Galea,
A Goel,
A Abbruzzese,
C R Boland,
S Venuta
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ABSTRACT: Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1). Pancreatic cancer frequently has a dysregulated p21(ras) pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21(ras). We found that ZOL induces growth inhibition (IC(50):10-50 micro M) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21(ras) signalling in cells exposed to ZOL and detected a reduction of p21(ras) and Raf-1 content and functional downregulation of the terminal enzyme ERK/MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras). These findings might be relevant for expanding application of BPs in cancer treatment.
British Journal of Cancer 07/2003; 88(12):1971-8. · 5.04 Impact Factor
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ABSTRACT: Interferon-alpha (IFNalpha) can induce apoptosis, a process regulated by a complex network of cell factors. Among these, eukaryotic initiation factor-5A (eIF-5A) is peculiar because its activity is modulated by the post-translational formation of the amino acid hypusine. Here we report the effects of IFNalpha and epidermal growth factor (EGF) on apoptosis and eIF-5A activity in human epidermoid oropharyngeal KB and lung H1355 cancer cells. We found that 48-h exposure to 1000 and 2000 IU/ml IFNalpha induced about 50% growth inhibition and apoptosis in H1355 and KB cells, respectively, and the addition of EGF completely antagonized this effect. When IFNalpha induced apoptosis, a hyperactivation of MEK-1 and ERK signalling and a decrease of the hypusine-containing form and, thus, of eIF-5A activity were recorded. The latter effect was again antagonized by the addition of EGF to IFNalpha-pretreated cells, probably through the activation of the EGF-->ERK-dependent pathway, since the addition of the specific MEK-1 inhibitor PD098059 abrogated the recovery of intracellular hypusine content induced by EGF in IFNalpha-pretreated cancer cells. Subsequently, we evaluated if the hypusine synthesis inhibitor (and eIF-5A inactivator) N1-guanyl-1,7-diaminoheptane (GC7) synergized with IFNalpha in the induction of cell growth inhibition and apoptosis. The analysis of the isobologram of IFNalpha and GC7 demonstrated a strong synergism between the two drugs in inducing cell growth inhibition. We also found that GC7 and IFNalpha had a synergistic effect on apoptosis. These data suggest that the apoptosis induced by IFNalpha could be regulated by eIF-5A that, therefore, could represent a useful target for the potentiation of IFNalpha antitumor activity.
Journal of Biochemistry 06/2003; 133(6):757-65. · 2.37 Impact Factor
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P Tassone,
P Tagliaferri,
A Perricelli,
S Blotta,
B Quaresima,
M L Martelli,
A Goel,
V Barbieri,
F Costanzo,
C R Boland,
S Venuta
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ABSTRACT: Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20-45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC(50)) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (P<0.005) more sensitive to cisplatin (CDDP) (IC(50) : 30-40 microM) compared with MCF-7 (IC(50) : 60-70 microM) and MDA-MB231 (IC(50) : 90-100 microM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC(50) : 45-50 microM) compared with MCF-7 (IC(50) : 1-5 microM) and MDA-MB231 (IC(50) : 5-10 microM) (P<0.02), as well as to paclitaxel (Tax) (IC(50) : >2 microM for HCC1937, 0.1-0.2 microM for MCF-7 and 0.01-0.02 microM for MDA-MB231) (P<0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/(WT)BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<0.02), and restored the sensitivity to Dox (P<0.05) and Tax (P<0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.
British Journal of Cancer 04/2003; 88(8):1285-91. · 5.04 Impact Factor
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M Caraglia,
P Tagliaferri,
M Marra,
G Giuberti,
A Budillon,
E Di Gennaro,
S Pepe,
G Vitale,
S Improta, P Tassone,
S Venuta,
A R Bianco,
A Abbruzzese
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ABSTRACT: The mechanisms of tumor cell resistance to interferon-alpha (IFNalpha) are at present mostly unsolved. We have previously demonstrated that IFNalpha induces apoptosis on epidermoid cancer cells and EGF antagonizes this effect. We have also found that IFNalpha-induced apoptosis depends upon activation of the NH(2)-terminal Jun kinase-1 (Jnk-1) and p(38) mitogen-activated protein kinase, and that these effects are also antagonized by EGF. At the same time, IFNalpha increases the expression and function of the epidermal growth factor receptor (EGF-R). Here we report that the apoptosis induced by IFNalpha occurs together with activation of caspases 3, 6 and 8 and that EGF also antagonizes this effect. On the basis of these results, we have hypothesized that the increased EGF-R expression and function could represent an inducible survival response that might protect tumor cells from apoptosis caused by IFNalpha via extracellular signal regulated kinase 1 and 2 (Erk-1/2) cascades. We have found an increased activity of Ras and Raf-1 in IFNalpha-treated cells. Moreover, IFNalpha induces a 50% increase of the phosphorylated isoforms and enzymatic activity of Erk-1/2. We have also demonstrated that the inhibition of Ras activity induced by the transfection of the dominant negative Ras plasmid RASN17 and the inhibition of Mek-1 with PD098059 strongly potentiates the apoptosis induced by IFNalpha. Moreover, the selective inhibition of this pathway abrogates the counteracting effect of EGF on the IFNalpha-induced apoptosis. All these findings suggest that epidermoid tumor cells counteract the IFNalpha-induced apoptosis through a survival pathway that involves the hyperactivation of the EGF-dependent Ras->Erk signalling. The selective targeting of this pathway appears to be a promising approach in order to enhance the antitumor activity of IFNalpha.
Cell Death and Differentiation 02/2003; 10(2):218-29. · 8.85 Impact Factor
