Cathepsin B inhibition interferes with metastatic potential of human melanoma: an in vitro and in vivo study

Molecular Cancer

Research

Caterina Catrical๠ Carlo Leonetti²  Marco Scarsella²  Walter Malorni³  Paola Matarrese³  Barbara Ascione³  Rosa Vona³  Laura Ciarlo³  Marco G Paggi⁴  Anna M Mileo⁴ 

[1] Department of Dermatology-Oncology, S. Gallicano Dermatological Institute, Via Elio Chianesi 53, 00144, Rome, Italy;Department of Experimental Chemotherapy, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy;Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy;Development of Therapeutic Programs, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy;

关键词: Melanoma;    Melanoma Cell;    Metastatic Melanoma;    Melanoma Cell Line;    Primary Melanoma;   

DOI  :  10.1186/1476-4598-9-207

 received in 2010-02-18, accepted in 2010-08-04,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCathepsins represent a group of proteases involved in determining the metastatic potential of cancer cells. Among these are cysteinyl- (e.g. cathepsin B and cathepsin L) and aspartyl-proteases (e.g. cathepsin D), normally present inside the lysosomes as inactive proenzymes. Once released in the extracellular space, cathepsins contribute to metastatic potential by facilitating cell migration and invasiveness.ResultsIn the present work we first evaluated, by in vitro procedures, the role of cathepsins B, L and D, in the remodeling, spreading and invasiveness of eight different cell lines: four primary and four metastatic melanoma cell lines. Among these, we considered two cell lines derived from a primary cutaneous melanoma and from a supraclavicular lymph node metastasis of the same patient. To this purpose, the effects of specific chemical inhibitors of these proteases, i.e. CA-074 and CA-074Me for cathepsin B, Cathepsin inhibitor II for cathepsin L, and Pepstatin A for cathepsin D, were evaluated. In addition, we also analyzed the effects of the biological inhibitors of these cathepsins, i.e. specific antibodies, on cell invasiveness. We found that i) cathepsin B, but not cathepsins L and D, was highly expressed at the surface of metastatic but not of primary melanoma cell lines and that ii) CA-074, or specific antibodies to cathepsin B, hindered metastatic cell spreading and dissemination, whereas neither chemical nor biological inhibitors of cathepsins D and L had significant effects. Accordingly, in vivo studies, i.e. in murine xenografts, demonstrated that CA-074 significantly reduced human melanoma growth and the number of artificial lung metastases.ConclusionsThese results suggest a reappraisal of the use of cathepsin B inhibitors (either chemical or biological) as innovative strategy in the management of metastatic melanoma disease.

【 授权许可】

CC BY   
© Matarrese et al; licensee BioMed Central Ltd. 2010