A squalamine derivative, NV669, as a novel PTP1B inhibitor: in vitro and in vivo effects on pancreatic and hepatic tumor growth
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Sylvie Carmona1,2, Jean-Michel Brunel3, Rénaté Bonier1,4, Véronique Sbarra1,5, Stéphane Robert6, Patrick Borentain1,7, Dominique Lombardo1, Eric Mas1,4 and René Gerolami1,7
1 Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de médecine, Marseille, France
2 Aix Marseille Univ, CNRS, INP, Institut de Neuro-Physiopathologie, Faculté de médecine, Marseille, France
3 Aix Marseille Univ, INSERM, SSA, MCT, Marseille, France
4 Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Centre de Recherche en Cancérologie de Marseille, Marseille, France
5 Aix Marseille Univ, INSERM, INRA, C2VN, Faculté de médecine, Marseille, France
6 Aix Marseille Univ, INSERM, INRA, C2VN AMUTICYT Core facility, Faculté de pharmacie, Marseille, France
7 Aix Marseille Univ, AP-HM, Assistance Publique des Hôpitaux de Marseille, Centre Hospitalo-Universitaire Timone, Service d’Hépato-Gastro-Entérologie, Marseille, France
Keywords: aminosterol; pancreas; liver; PTP1B; cancer
Abbreviations: HCC: hepatocellular carcinoma; PDAC: pancreatic adenocarcinoma; PTB1B: protein tyrosine phosphatase 1B
Received: October 29, 2017 Accepted: October 02, 2019 Published: November 19, 2019
NV669 is an aminosterol derived from squalamine found to possess strong anticancer effects. The aim of this study was to investigate NV669’s beneficial effects on human pancreatic and hepatic cancer models and to decipher the cellular and molecular mechanisms involved in tumor growth decrease upon treatment with NV669.
Pancreatic (BxPC3, MiaPaCa-2) and hepatic (HepG2, Huh7) cancer cells were treated with NV669, and the effects recorded on proliferation, cell cycle and death. Results showed that NV669 inhibited the viability of cancer cells, induced cell cycle arrest and subsequently promoted apoptosis. This was accompanied by a decrease in the expression of cyclin B1 and phosphorylated Cdk1 and by a cleavage of pro-apoptotic caspase-8 and PARP-1. Taken together, our studies showed that NV669 inhibits the proliferation of pancreatic and hepatic cancer cells through the regulation of G2/M phase transition via the cyclin B1-Cdk1 complex.
In vitro NV669 inhibits PTP1B activity and FAK expression. NV669 impacts on the expression of adhesion molecules CDH-1, -2 and -3 in BxPC3 and Huh7 lines that form cell monolayers. Consecutively NV669 induces cell detachment. This suggests that NV669 by inhibiting PTP1B induces cell detachment and apoptosis.
Subsequently, our in vivo results showed that NV669 inhibited the growth of pancreatic and hepatic tumor xenografts with a significant cell cycle arrest in pre-mitotic phase and an increase of tumor cell apoptosis. Therefore, NV669 may serve as an alternative anticancer agent, used alone or in association with other medications, for the treatment of pancreatic adenocarcinoma and hepatocellular carcinoma.
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