Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are common solid organ malignancies worldwide [1]
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
Our results showed that NV669 inhibited significantly the viability of all cancer cell lines in a doseand time-dependent manner (Figure 1C)
Summary
Pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are common solid organ malignancies worldwide (https://www.cancer. org/content/dam/cancer-org/research/cancer-facts-andstatistics/annual-cancer-facts-and-figures/2018/cancerfacts-and-figures-2018.pdf) [1]. The benefits of systemic therapies such as gemcitabine (cytosine analogue) and sorafenib (multikinase inhibitor), respectively for pancreatic and liver cancer, remain low in these patients [2,3,4]. Many studies have examined the antitumoral effect of squalamine, a natural aminosterol, initially isolated from the liver of the shark Squalus acanthias [5]. Squalamine is chemically synthesized [6] for it clinical applications and known to have a strong anti-angiogenic activity in vitro and in vivo [7, 8]. The antiangiogenic activity of squalamine was confirmed in various tumor xenograft models. Squalamine was assessed in phases I and II of clinical trials on lung cancer [14, 15]. In this study we synthesized squalamine analogues with the expectation to obtain a more efficacious derivative
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