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A New Synthetic Spiroketal: Studies on Antitumor Activity on Murine Melanoma Model In Vivo and Mechanism of Action In Vitro

[ Vol. 19 , Issue. 4 ]

Author(s):

Maria P. Fuggetta*, Pietro Spanu*, Fausta Ulgheri, Francesco Deligia, Paola Carta, Alberto Mannu, Veronica Trotta, Rosanna De Cicco, Adriano Barra, Enrica Zona and Franco Morelli*   Pages 567 - 578 ( 12 )

Abstract:


Background: In a previous study, we synthesised a new spiroketal derivative, inspired to natural products, that has shown high antiproliferative activity, potent telomerase inhibition and proapoptotic activity on several human cell lines.

Objective: This work focused on the study of in vivo antitumor effect of this synthetic spiroketal on a murine melanoma model. In order to shed additional light on the origin of the antitumor effect, in vitro studies were performed.

Methods: Spiroketal was administered to B16F10 melanoma mice at a dose of 5 mg/Kg body weight via intraperitoneum at alternate days for 15 days. Tumor volume measures were made every 2 days starting after 12 days from cells injection. The effects of the spiroketal on tumor growth inhibition, apoptosis induction, and cell cycle modification were investigated in vitro on B16 cells. HIF1α gene expression, the inhibition of cells migration and the changes induced in cytoskeleton conformation were evaluated.

Results: Spiroketal displayed proapoptotic activity and high antitumor activity in B16 cells with nanomolar IC50. Moreover it has shown to inhibit cell migration, to strongly reduce the HIF1α expression and to induce strongly deterioration of cytoskeleton structure. A potent dose-dependent antitumor efficacy in syngenic B16/C57BL/6J murine model of melanoma was observed with the suppression of tumor growth by an average of 90% at a dose of 5 mg/kg.

Conclusion: The synthesized spiroketal shows high antitumor activity in the B16 cells in vitro at nM concentration and a dose-dependent antitumor efficacy in syngenic B16/C57BL/6J mice. The results suggest that this natural product inspired spiroketal may have a potential application in melanoma therapy.

Keywords:

Spiroketals, anticancer, melanoma, apoptosis, HIF1α, cell migration.

Affiliation:

Istituto di Farmacologia Traslazionale-Consiglio Nazionale delle Ricerche, Roma, Istituto di Chimica Biomolecolare- Consiglio Nazionale delle Ricerche, Sassari, Istituto di Chimica Biomolecolare- Consiglio Nazionale delle Ricerche, Sassari, Istituto di Chimica Biomolecolare- Consiglio Nazionale delle Ricerche, Sassari, Istituto di Chimica Biomolecolare- Consiglio Nazionale delle Ricerche, Sassari, Istituto di Chimica Biomolecolare- Consiglio Nazionale delle Ricerche, Sassari, Istituto di Genetica e Biofisica A. Buzzati Traverso-Consiglio Nazionale delle Ricerche, Napoli, Istituto di Genetica e Biofisica A. Buzzati Traverso-Consiglio Nazionale delle Ricerche, Napoli, Istituto di Genetica e Biofisica A. Buzzati Traverso-Consiglio Nazionale delle Ricerche, Napoli, Istituto di Genetica e Biofisica A. Buzzati Traverso-Consiglio Nazionale delle Ricerche, Napoli, Istituto di Genetica e Biofisica A. Buzzati Traverso-Consiglio Nazionale delle Ricerche, Napoli

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