INVESTIGADORES
ALONSO Daniel Fernando
congresos y reuniones científicas
Título:
Antimigratory and antimetastatic activity of novel anti-Rac nucleoside compounds in a mouse mammary carcinoma model
Autor/es:
LORENZANO MENNA P; ZINNI A; IGLESIAS L; IRIBARREN A; ALONSO DF; GOMEZ DE
Lugar:
Los Angeles, USA
Reunión:
Congreso; Annual Meeting 2007 of the American Association for Cancer ResearchL; 2007
Institución organizadora:
American Association for Cancer Research
Resumen:
The Rho family of small GTPases includes at least 23 molecules with structural and functional relation to Ras oncoprotein. In the last years many evidences have been accumulated about the role of Rho-GTPases in malignant transformation and tumorigenesis. Previously, we have demonstrated that â2-chimaerin, a specific Rac1 inhibitor, is a key modulator of tumor invasion and metastasis in the highly aggressive F3II mouse mammary carcinoma model (Lorenzano Menna et al. Cancer Res. 63: 2284-91, 2003). The central aim of this work was to evaluate the antitumor properties of small organic compounds with high affinity for the nucleoside binding site of the Rho-GTPase Rac1. A panel of guanosine and inosine analogs was designed and synthesized using chemo-enzymatic methodologies. In vitro antitumor activity of compounds in log-phase growing F3II cells was studied by a colorimetric method, and the IC50 values were calculated. Effect on tumor cell migration was examined by the wound assay on confluent F3II monolayers. Rac activity was evaluated using the pull-down assay followed by western blot. To study the effects of compounds on formation and growth of blood-borne metastasis, 2 x 105 F3II viable cells were injected into the lateral tail vein of syngeneic Balb/c mice and surface lung nodules were measured 21 days later. Compounds designated N-101 (2´,3´,5´-di-O-acetylguanosine), N-104 (6-chloro-2´,3´,5´-tri-O-acetylpurine riboside) and N-205 (5´-hexanoyl-2´,3´-di-O-acetylguanosine) showed cytostatic activity with IC50 values in the low micromolar range, while other compounds tested had no relevant inhibitory activity on mammary tumor cells. N-101, N-104 and N-205 inhibited F3II cell migration at doses of 1-10 µM, without cytotoxic effects. Furthermore, the antimigratory effect was associated with a dose-dependent decrease of intracellular Rac-GTP levels. Daily treatment with intraperitoneal doses of 5 mg/kg of N-205 was well tolerated in female mice, and significantly reduced the number of metastatic lung nodules. Our results demonstrated the antitumor properties of novel anti-Rac nucleoside analogs in a preclinical animal model, suggesting their potential utility in breast cancer treatment.