title: The HIV-protease inhibitor saquinavir reduces proliferation, invasion and clonogenicity in cervical cancer cell lines.
abstract: Innovative therapies in cervical cancer (CC) remain a priority. Recent data indicate that human immunodeficiency virus (HIV)-protease inhibitors used in highly active antiretroviral therapy can exert direct antitumor activities also in HIV-free preclinical and clinical models. The aim of the present study was to evaluate the antineoplastic effects of various HIV-protease inhibitors (indinavir, ritonavir and saquinavir) on primary and established CC cell lines. Two CC cell lines established in our laboratory and four commercially available CC cell lines were treated with indinavir, ritonavir and saquinavir at different concentrations and for different times. Proliferation, clonogenicity and radiosensitivity were evaluated by crystal violet staining. Proteasomal activities were assessed using a cell-based assay and immunoblotting. Cell cycle was analyzed by propidium iodide staining and flow cytometric analysis. Invasion was tested with Matrigel chambers. At-test for paired samples was used for statistical analysis. In all cell lines, saquinavir was more effective than ritonavir in reducing cell proliferation and inhibiting proteasomal activities (P≤0.05). Conversely, indinavir exerted a negligible effect. The saquinavir concentrations required to modulate the proteasome activities were higher than those observed to be effective in inhibiting cell proliferation. In HeLa cells, saquinavir was strongly effective in inhibiting cell invasion and clonogenicity (P≤0.05) at concentrations much lower than those required to perturb proteasomal activities. Saquinavir did not contribute to increase the sensitivity of HeLa cells to X-rays. In conclusion, the present results demonstrate that saquinavir is able to significantly reduce cell proliferation, cell invasion and clonogenicity in a proteasome-independent manner inin vitromodels of CC, and suggest that saquinavir could be a promising CC therapeutic agent.
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bandiera
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Todeschini
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romani
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Zanotti
authors.affiliation: Department of Oncology, Flow Cytometry Unit, IRCCS - 'Mario Negri' Institute for Pharmacological Research, I-20156 Milan, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.affiliation: Department of Oncology, Flow Cytometry Unit, IRCCS - 'Mario Negri' Institute for Pharmacological Research, I-20156 Milan, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Colmegna
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Bignotti
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Alessandro Davide
authors.initials: AD
authors.lastname: Santin
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Sartori
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Franco Edoardo
authors.initials: FE
authors.lastname: Odicino
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Pecorelli
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Renata Alessandra
authors.initials: RA
authors.lastname: Tassi
authors.affiliation: Department of Obstetrics and Gynecology, 'Angelo Nocivelli' Institute for Molecular Medicine, University of Brescia, I-25123 Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ravaggi
keywords: HIV-protease inhibitors; cell lines; cervical cancer; proteasomal activities; saquinavir