INTRODUCTION Microtubules are highly dynamic cytoskeletal fibers that are composed of &#945;/&#946; tubulin and play an important role in many physiological processes, especially mitosis and cell division. Their importance in these processes makes them an important target for anticancer therapy. The well characterized antimitotic drugs that have proven clinical efficacy both in solid tumors and in hematological malignancies, such as the taxanes, and Vinca alkaloids (vincristine, vinblastine,etc) bind to tubulin. Recently the antitumor activity towards ovarian cancer cells of a new class of indole-derivatives, the substituted E-3-(2-chloro-3indolylmethylene)1,3-dihydroindol-2-ones, has been reported (1). In this work we assessed the antiproliferative activity of three new synthesized indole-derivatives in IGROV-1, a human ovarian adenocarcinoma cell line. MATERIALS AND METHODS Compounds under test were dissolved in DMSO. For treatments the IGROV-1cells were plated at 2x10<sup>4</sup> cells/cm<sup>2</sup> in Petri dishes, and after 24 hr the medium was removed and fresh medium containing the drugs was added. The IC<sub>50</sub> was determined by MTT assay. Indole-derivatives antiproliferative effect was assayed by measuring <sup>3</sup>H-thymidine incorporation. Cell cycle distribution was evaluated by flow citometry. RESULTS In our experimental model the IC<sub>50</sub> for compounds under test was 6µM. <sup>3</sup>H-thymidine incorporation after treatment was reduced by about 85% with respect to control: all molecules in IGROV-1 cells produced a cytostatic effect, as revealed by the mitotic index. Moreover these agents induced an irreversible antiproliferative effect as evidenced by time-response curve. To monitor cell cycle progression the samples were analyzed by flow cytometry and it was demonstrated that two of the three compounds determine an arrest in G2/M phase, similarly to vincristine, chosen as positive control because its structure contains two indoles. Further studies are in progress to investigate if the drugs under test affect tubulin posttranslational modifications, such as phosphorylation and/or acetylation. References Substituted E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with antitumor activity. Andreani A.,et al. BMC 2004, 12, 1121

ANTITUMOR ACTIVITY OF INDOLE-DERIVATIVES IN THE HUMAN OVARIAN CANCER CELL LINE IGROV-1

CAPPADONE, CONCETTINA;CALONGHI, NATALIA;FARRUGGIA, GIOVANNA;MANGANO, CHIARA;PAGNOTTA, ELEONORA;PAROLIN, CAROLA ELEONORA;MASOTTI, LANFRANCO
2006

Abstract

INTRODUCTION Microtubules are highly dynamic cytoskeletal fibers that are composed of α/β tubulin and play an important role in many physiological processes, especially mitosis and cell division. Their importance in these processes makes them an important target for anticancer therapy. The well characterized antimitotic drugs that have proven clinical efficacy both in solid tumors and in hematological malignancies, such as the taxanes, and Vinca alkaloids (vincristine, vinblastine,etc) bind to tubulin. Recently the antitumor activity towards ovarian cancer cells of a new class of indole-derivatives, the substituted E-3-(2-chloro-3indolylmethylene)1,3-dihydroindol-2-ones, has been reported (1). In this work we assessed the antiproliferative activity of three new synthesized indole-derivatives in IGROV-1, a human ovarian adenocarcinoma cell line. MATERIALS AND METHODS Compounds under test were dissolved in DMSO. For treatments the IGROV-1cells were plated at 2x104 cells/cm2 in Petri dishes, and after 24 hr the medium was removed and fresh medium containing the drugs was added. The IC50 was determined by MTT assay. Indole-derivatives antiproliferative effect was assayed by measuring 3H-thymidine incorporation. Cell cycle distribution was evaluated by flow citometry. RESULTS In our experimental model the IC50 for compounds under test was 6µM. 3H-thymidine incorporation after treatment was reduced by about 85% with respect to control: all molecules in IGROV-1 cells produced a cytostatic effect, as revealed by the mitotic index. Moreover these agents induced an irreversible antiproliferative effect as evidenced by time-response curve. To monitor cell cycle progression the samples were analyzed by flow cytometry and it was demonstrated that two of the three compounds determine an arrest in G2/M phase, similarly to vincristine, chosen as positive control because its structure contains two indoles. Further studies are in progress to investigate if the drugs under test affect tubulin posttranslational modifications, such as phosphorylation and/or acetylation. References Substituted E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with antitumor activity. Andreani A.,et al. BMC 2004, 12, 1121
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ITALIAN JOURNAL OF BIOCHEMISTRY
Cappadone C.; Calonghi N.; Farruggia G.; Mangano C.; Pagnotta E.; Parolin C.; Masotti L.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/57098
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