BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although hepatectomy and transplantation have significantly improved survival, there is no effective chemotherapeutic treatment for HCC and its prognosis remains poor. Sustained activation of telomerase is essential for the growth and progression of HCC, suggesting that telomerase is a rational target for HCC therapy. Therefore, we developed a thymidine analogue pro-drug, acycloguanosyl-5'-thymidyltriphosphate (ACV-TP-T), which is specifically activated by telomerase in HCC cells and investigated its anti-tumour efficacy. METHODS: First, we verified in vitro whether ACV-TP-T was a telomerase substrate. Second, we evaluated proliferation and apoptosis in murine (Hepa1-6) and human (Hep3B, HuH7, HepG2) hepatic cancer cells treated with ACV-TP-T. Next, we tested the in vivo treatment efficacy in HBV transgenic mice that spontaneously develop hepatic tumours, and in a syngeneic orthotopic murine model where HCC cells were implanted directly in the liver. RESULTS: In vitro characterization provided direct evidence that the pro-drug was actively metabolized in liver cancer cells by telomerase to release the active form of acyclovir. Alterations in cell cycle and apoptosis were observed following in vitro treatment with ACV-TP-T. In the transgenic and orthotopic mouse models, treatment with ACV-TP-T reduced tumour growth, increased apoptosis, and reduced the proliferation of tumour cells. CONCLUSIONS: ACV-TP-T is activated by telomerase in HCC cells and releases active acyclovir that reduces proliferation and induces apoptosis in human and murine liver cancer cells. This pro-drug holds a great promise for the treatment of HCC.

Telomerase activated thymidine analogue pro-drug is a new molecule targeting hepatocellular carcinoma / Mirko Tarocchi;Simone Polvani;Anna Julie Peired;Giada Marroncini;Massimo Calamante;Elisabetta Ceni;Daniela Rhodes;Tommaso Mello;Giuseppe Pieraccini;Alessandro Quattrone;Claudio Luchinat;Andrea Galli. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - STAMPA. - 61:(2014), pp. 1064-1072. [10.1016/j.jhep.2014.05.027]

Telomerase activated thymidine analogue pro-drug is a new molecule targeting hepatocellular carcinoma

TAROCCHI, MIRKO;POLVANI, SIMONE;PEIRED, ANNA JULIE;MARRONCINI, GIADA;CALAMANTE, MASSIMO;CENI, ELISABETTA;MELLO, TOMMASO;PIERACCINI, GIUSEPPE;LUCHINAT, CLAUDIO;GALLI, ANDREA
2014

Abstract

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although hepatectomy and transplantation have significantly improved survival, there is no effective chemotherapeutic treatment for HCC and its prognosis remains poor. Sustained activation of telomerase is essential for the growth and progression of HCC, suggesting that telomerase is a rational target for HCC therapy. Therefore, we developed a thymidine analogue pro-drug, acycloguanosyl-5'-thymidyltriphosphate (ACV-TP-T), which is specifically activated by telomerase in HCC cells and investigated its anti-tumour efficacy. METHODS: First, we verified in vitro whether ACV-TP-T was a telomerase substrate. Second, we evaluated proliferation and apoptosis in murine (Hepa1-6) and human (Hep3B, HuH7, HepG2) hepatic cancer cells treated with ACV-TP-T. Next, we tested the in vivo treatment efficacy in HBV transgenic mice that spontaneously develop hepatic tumours, and in a syngeneic orthotopic murine model where HCC cells were implanted directly in the liver. RESULTS: In vitro characterization provided direct evidence that the pro-drug was actively metabolized in liver cancer cells by telomerase to release the active form of acyclovir. Alterations in cell cycle and apoptosis were observed following in vitro treatment with ACV-TP-T. In the transgenic and orthotopic mouse models, treatment with ACV-TP-T reduced tumour growth, increased apoptosis, and reduced the proliferation of tumour cells. CONCLUSIONS: ACV-TP-T is activated by telomerase in HCC cells and releases active acyclovir that reduces proliferation and induces apoptosis in human and murine liver cancer cells. This pro-drug holds a great promise for the treatment of HCC.
2014
61
1064
1072
Mirko Tarocchi;Simone Polvani;Anna Julie Peired;Giada Marroncini;Massimo Calamante;Elisabetta Ceni;Daniela Rhodes;Tommaso Mello;Giuseppe Pieraccini;Alessandro Quattrone;Claudio Luchinat;Andrea Galli
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/931335
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