Doxorubicin is a potent anti-cancer agent of the anthracycline family widely used in the chemotherapeutic treatment of different tumors. The exact mechanism by which Doxorubicin induces death of neoplastic cells remains to be fully elucidated. Although anthracycline can exert cytotoxic action by directly liberating free oxygen radicals, Doxorubicin was also shown to bind and inhibit proteasomes. Notably, proteasomal inhibition is known to induce apoptosis of rapidly proliferating cells and, consistent with this notion, proteasome inhibitors are emerging as powerful tools against many tumors, especially plasma cell malignancies. Since recent work from our lab demonstrated an enhanced expression and activities of immunoproteasomes in feline injection-site sarcoma (FISS)1, a spontaneously occurring tumor of cats that is an informative model for the study of tumour biology in other species, including humans, we undertook this study to assess if clinical Doxorubicin treatment induces modulation of proteasomes level and functions in vivo. To this end, we measured proteasomal subunits expression levels and catalytic activities in tissue extracts from primary fibrosarcoma lesions and related healthy subcutis of nine cats affected by FISS who received standard Doxorubicin treatment. By this approach we demonstrated that the enhanced immunoproteasomal expression and enzymatic activity characteristic of FISS is not at all affected by standard pre–surgery Doxorubicin administration. This unexpected finding might account for the reported low clinical effectiveness of such a treatment in FISS and provides the rationale for developing new therapeutic protocols aimed at achieving a better proteasomal inhibition in this and others poorly Doxorubicin-sensitive tumors.

Doxorubicin treatment does not affect enhanced immunoproteasome expression and activities in feline-injection site sarcoma

CERRUTI, Fulvia;MARTANO, Marina;BOLLO, Enrico;MORELLO, Emanuela Maria;BRUNO, Renato;BURACCO, Paolo;CASCIO, Paolo
2008-01-01

Abstract

Doxorubicin is a potent anti-cancer agent of the anthracycline family widely used in the chemotherapeutic treatment of different tumors. The exact mechanism by which Doxorubicin induces death of neoplastic cells remains to be fully elucidated. Although anthracycline can exert cytotoxic action by directly liberating free oxygen radicals, Doxorubicin was also shown to bind and inhibit proteasomes. Notably, proteasomal inhibition is known to induce apoptosis of rapidly proliferating cells and, consistent with this notion, proteasome inhibitors are emerging as powerful tools against many tumors, especially plasma cell malignancies. Since recent work from our lab demonstrated an enhanced expression and activities of immunoproteasomes in feline injection-site sarcoma (FISS)1, a spontaneously occurring tumor of cats that is an informative model for the study of tumour biology in other species, including humans, we undertook this study to assess if clinical Doxorubicin treatment induces modulation of proteasomes level and functions in vivo. To this end, we measured proteasomal subunits expression levels and catalytic activities in tissue extracts from primary fibrosarcoma lesions and related healthy subcutis of nine cats affected by FISS who received standard Doxorubicin treatment. By this approach we demonstrated that the enhanced immunoproteasomal expression and enzymatic activity characteristic of FISS is not at all affected by standard pre–surgery Doxorubicin administration. This unexpected finding might account for the reported low clinical effectiveness of such a treatment in FISS and provides the rationale for developing new therapeutic protocols aimed at achieving a better proteasomal inhibition in this and others poorly Doxorubicin-sensitive tumors.
2008
2° Congresso dei Biotecnologi – Sezione Piemonte
Molecular Biotechnology Center (MBC)
29 February – 1 March, 2008
Atti del 2° Congresso dei Biotecnologi – Sezione Piemonte
A.N.B.I.
60
60
Immunoproteasome; Doxorubicin; FISS
F. Cerruti; M. Martano; C. Petterino; E. Bollo; E. Morello; R. Bruno; P. Buracco; P. Cascio
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/65779
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact