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AOU Senese

Pub Med

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Patologia Generale

Università degli Studi di Siena
Dip. Fisiopatologia, Medicina Sperimentale e Sanità Pubblica – Sez. Patologia Generale
Via A. Moro, 53100 Siena
Tel: 0577 234006
Fax: 0577 234009
E-mail: maellaro@unisi.it
Ricercatore responsabile: Prof. Emilia Maellaro
Collaboratori di laboratorio: Dr. Barbara Del Bello, Dr. Daniele Moretti

Progetti Specifici

At present, the main fields of interest are briefly reported as follows:

  1. Biochemical and molecular mechanisms of drug-induced apoptosis in melanoma cells.
    In the last few years, we aimed at characterizing some biochemical mechanisms occurring during cisplatin (CDDP)-induced apoptosis of human metastatic melanoma cells. In this experimental model, we have recently demonstrated (Del Bello et al., 2006) that ubiquitous calpains play a key role in apoptosis: they are early activated, well before activation of effector caspases, and their pharmacological inhibition, downregulating the cisplatin-induced p53 activation, significantly protects from cell death.
    Against this background, the current work aims to investigate not yet explored calpain-mediated processes, responsible for cisplatin-induced apoptosis. In particular, we are studying i) the mechanisms of calpain-mediated p53 modulation (gene expression and protein stabilization); ii) novel calpain-mediated apoptotic pathways, including mitochondrial AIF release and a "proteolytic cross-talk" with autophagy; iii) changes in sensitivity to apoptosis by modulating calpain expression (overexpression or silencing); iv) possible correlations between calpain expression levels in human melanoma biopsies and clinical-pathological parameters of staging (in collaboration with Prof. Miracco and Dr. Biagioli, University of Siena). Furthermore, a very novel aspect is under investigation, that is the ectopic expression of muscle-specific calpain (calpain 3) in melanoma cell lines and biopsies. In particular, the research is devoted to find possible correlations i) between calpain 3 expression (and its intracellular localization) and response to cytotoxic drugs (in melanoma cell lines), ii) between calpain 3 and conventional calpains, and iii) between calpain 3 expression and the clinical-pathological parameters of staging (in human melanoma biopsies, also compared to normal naevi). The appraisal of these processes can contribute to dissect the pathways of melanoma apoptotic machinery along with the mechanisms of chemoresistance, thus suggesting new potential targets for rationally designed therapeutic strategies.
    Del Bello B, Moretti D, Gamberucci A and Maellaro E. Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status Oncogene 26(19), 2717-26, 2007.
  2. Efficacy of new somatostatin analogs to induce cell grow inhibition and apoptosis in tumour cells expressing somatostatin receptors.
    This novel project, in collaboration with Prof. Mariani (University of Pisa), is aimed to study newly designed somatostatin analogues, conjugated with (radioactive) metals/azamacrocycles complexes, stable in a physiological milieu, and provided with high affinity and selectivity for a single somatostatin receptor subtype. Such analogues, synthesised and supplied by Prof. Ginanneschi (University of Florence), will be studied for their ability to induce cell proliferation inhibition and apoptotic cell death in tumour cells expressing somatostatin receptors. Among such tumour cells, the present Research Unit will study the biochemical and molecular pathways of cell death in thyroid carcinoma cells, where no study has been done up till now on apoptosis induced by somatostatin analogues; in particular, our interest will be focused on follicular cancer cells, which in vivo (mainly in metastases) may undergo a “de-differentiation" process leading to loss of iodine-concentrating capability, with the consequent inefficacy of radioiodine therapy.

Grants

  • 2001: assegnazione Quota Progetti Piano di Ateneo per la Ricerca (PAR) (durata 15 mesi); responsabile Prof. E. Maellaro; titolo "Ruolo di Bcl-2 nella regolazione dell'apoptosi: frammentazione proteolitica di Bcl-2 e modulazione del fattore di trascrizione NF-kB"
  • 2001: progetto AIRC (durata triennale); coordinatore Prof. A. Pompella, Prof. E. Maellaro tra i partecipanti; titolo "γ-glutamyl trnspeptidase of cancer cells: redox effects on signal transduction, apoptosis and drug resistance".
  • 2002: assegnazione Quota Progetti Piano di Ateneo per la Ricerca (PAR) (durata biennale); responsabile Prof. E. Maellaro; titolo "Meccanismi redox di modulazione dell'apoptosi in cellule neoplastiche: ruolo della γ-glutamil transpeptidasi".
  • 2004: progetto PRIN (durata biennale); coordinatore nazionale Prof. M. Santucci, coordinatore locale Prof. C. Miracco, Prof. E. Maellaro e Dr. B. Del Bello tra i partecipanti; titolo mod. B "Ruolo dei macrofagi su stato redox, risposta apoptotica, farmacoresistenza e lunghezza dei telomeri delle cellule tumorali nel melanoma cutaneo. Correlazioni biologiche e prognostiche".
  • 2005: assegnazione Quota Progetti Piano di Ateneo per la Ricerca (PAR) (durata biennale); responsabile Prof. L. Ciccoli, Prof. E. Maellaro tra i partecipanti; titolo "Alterazioni morfo-funzionali di eritrociti, monociti, piastrine e complicanze vascolari nel diabete di tipo 2".
  • 2005: assegnazione Quota Progetti Piano di Ateneo per la Ricerca (PAR) (durata biennale); responsabile Prof. C. Miracco; Dr. B. Del Bello tra i partecipanti; titolo "Metilazione del DNA, profilo immunologico, telomerasi/telomeri nel melanoma cutaneo umano: studi in vitro e in vivo ed implicazioni terapeutiche".
  • 2005: progetto PRIN (durata biennale); coordinatore nazionale Prof. G. Mariani, coordinatore locale Prof. M. Ferrali, Dr. B. Del Bello tra i partecipanti; titolo mod. B "Caratterizzazione chimico-fisica e teorico-computazionale, e studio degli effetti biologici di tetra-aza macrocicli funzionalizzati per il trasporto di radionuclidi di rame e di renio in diagnostica e oncologia clinica".

Collaborazioni

  • Università degli Studi di Siena: Dip. Patologia Umana ed Oncologia (Prof. Miracco, Prof. Luzi), Dip. Medicina Clinica e Scienze Immunologiche (Dr. Biagioli); Dip. Fisiopatologia, Medicina Sperimentale e Sanità Pubblica – Sez. Patologia Generale (Prof. Ferrali, Dr. Gamberucci).
  • Università degli Studi di Pisa: Dip. Patologia Sperimentale & BME - Sez.. Patol. Generale (Prof. Pompella, Prof. Paolicchi, Prof. Casini); Centro Regionale Medicina Nucleare – Dip. Oncologia, Trapianti e Nuove Tecnologie in Medicina (Prof. Mariani, Dr. Erba).
  • Università degli Studi di Firenze: Dip. Chimica Organica "Ugo Schiff" (Prof. Ginanneschi); Dip. Scienze Biochimiche (Dr. Marzocchini).

Pubblicazioni (dal 2001)

  1. B. Del Bello, M.A. Valentini, F. Zunino, M. Comporti and E. Maellaro. Cleavage of Bcl-2 in oxidant-and cisplatin-induced apoptosis in melanoma cells. Oncogene 20, 4591-4595, 2001.
  2. A. Paolicchi, S. Dominici, L. Pieri, E. Maellaro and A. Pompella. Glutathione catabolism as a signaling mechanism. Biochem. Pharmacol. 64, 1027-1035, 2002.
  3. L. Pieri, S. Dominici, B. Del Bello, E. Maellaro, M. Comporti, A. Paolicchi and A. Pompella. Redox modulation of protein kinase/phosphatase balance in melanoma cells: the role of endogenous and γ-glutamyltransferase-dependent H2O2 production. Biochim. Biophys. Acta 1621, 76-83, 2003.
  4. E. Maellaro, L. Pacenti, B. Del Bello, M.A. Valentini, P. Mangiavacchi, C. De Felice, P. Rubegni, P. Luzi and C. Miracco. Different effects of interferon-α?on melanoma cells lines: a study of Telomerase Reverse Transcriptase, telomerase activity, and apoptosis. Brit. J. Dermatol 148(6), 1115-1124, 2003.
  5. C. Miracco, E. Maellaro, L. Pacenti, B. Del Bello, M.A. Valentini, P. Rubegni, L. Pirtoli, C. Volpi, R. Santopietro and P. Tosi. Evaluation of MDR1, LRP, MRP, and topoisomerase IIα gene mRNA transcripts before and after interferon-α, and correlation with the mRNA expression level of the telomerase subunits hTERT and TEP1 in five unselected human melanoma cell lines. Int. J. Onc. 23(1), 213-320, 2003.
  6. S. Dominici, A. Paolicchi, E. Lorenzini, E. Maellaro, M. Comporti, L. Pieri, G. Minotti and A. Pompella. γ-Glutamyltransferase-Dependent Prooxidant Reactions: a Factor in Multiple Processes . BioFactors 17(1-4), 187-198, 2003.
  7. B. Del Bello, M.A. Valentini, M. Comporti and E. Maellaro. Cisplatin-induced Apoptosis in Melanoma Cells: Role of Caspase-3 and –7 in Apaf-1 Proteolytic Cleavage and in Execution of the Degradative Phases. Ann. N.Y. Acad. Sci. 1010, 200-204, 2003.
  8. B. Del Bello, M.A. Valentini, M. Comporti and E. Maellaro. Role of caspase-3 and –7 in Apaf-1 proteolytic cleavage and degradation events during cisplatin-induced apoptosis in melanoma cells. Exp. Cell Res. 293, 302-310, 2004.
  9. E. Grassilli, A. Ballabeni, E. Maellaro, B. Del Bello, and K. Helin. Distinct pathways of serine proteases and caspases activation are simultaneously triggered by doxorubicin and require Myc function. J. Biol. Chem. 279(20), 21318-21326, 2004.
  10. Dominici S, Paolicchi A, Corti A, Maellaro E, Pompella A. Prooxidant reactions promoted by soluble and cell-bound gamma-glutamyltransferase activity. Methods Enzymol. 401, 484-501, 2005.
  11. Miracco C, De Nisi MC, Arcuri F, Cosci E, Pacenti L, Toscano M, Lalinga AV, Biagioli M, Rubegni P, Vatti R, Maellaro E, Del Bello B, Massi D, Luzi P, Tosi P. Macrophage migration inhibitory factor protein and mRNA expression in cutaneous melanocytic tumours. Int. J. Oncol. 28(2), 345-52, 2006.
  12. Del Bello B, Moretti D, Gamberucci A and Maellaro E. Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status. Oncogene 26(19), 2717-2726, 2007.