Antimetastatic and Antitumor Activities of Orally Administered NAX014 Compound in a Murine Model of HER2-Positive Breast Cancer

Abstract

The natural isoquinoline alkaloid Berberine (BBR) has been shown to possess several therapeutic effects, including anticancer activity. Different BBR derivatives have been designed and synthesized in order to obtain new compounds with enhanced anticancer efficacy. We previously showed that intraperitoneal (IP) administration of the BBR-derived NAX014 compound was able to counteract HER-2 overexpressing mammary tumors onset and progression in transgenic mice. However, the IP administration was found to induce organ toxicity at doses higher than 2.5 mg/Kg. In this study, we evaluated the effect of intragastric (IG) administration of 20 mg/kg of NAX014 on both safety and anticancer efficacy in HER-2/neu transgenic mice. Furthermore, cancer cell dissemination and migration, tumor cell senescence and immunological changes were examined. Our results demonstrated that IG NAX014 administration delayed the onset of mammary tumors with no negative effects on health and survival. NAX014 reduced HER-2 overexpressing BC cells migration in vitro and the frequency of lung metastasis in HER-2/neu transgenic mice. A statistically significant increase of senescence-associated p16 expression was observed in tumors from NAX014-treated mice, and the induction of cell senescence was observed in HER-2 overexpressing BC cells after in vitro treatment with NAX014. Although NAX014 did not modulate the presence of tumor-infiltrating lymphocytes, the level of circulating TNF-α and VEGF was found to be reduced in NAX014-treated mice. The overall results address the NAX014 compound as potential tool for therapeutic strategies against HER-2 overexpressing breast cancer.

Antitumor Effect of Berberine Analogs in a Canine Mammary Tumor Cell Line and in Zebrafish Reporters via Wnt/β-Catenin and Hippo Pathways

“…In a recent study, Pierpaoli and collaborators explored the efficacy of the oral administration of a BBR derivative (NAX014) in a mouse model of HER2-overexpressing breast cancer. The authors showed no signs of toxicity after the oral administration of a high dose of the compound, suggesting its safety [56].…”

“…The analogs under investigation possess aromatic groups attached to the 13-position of the parent alkaloid skeleton through a hydrocarbon linker [49]. Their effects on Wnt/β-catenin signaling [50] and on some relevant human tumor types have been reported, both in vitro [36,[51][52][53][54][55] and in vivo [41,56]. and treatment of colon cancer through the inhibition of Wnt/β-catenin signaling [40] and in exerting anticancer activity, delaying the development of MTs in transgenic mice for the HER-2/neu oncogene [41][42][43].…”

“…The analogs under investigation possess aromatic groups attached to the 13-position of the parent alkaloid skeleton through a hydrocarbon linker [49]. Their effects on Wnt/β-catenin signaling [50] and on some relevant human tumor types have been reported, both in vitro [36,[51][52][53][54][55] and in vivo [41,56]. To elucidate the mechanism involved in the antitumor effect of BBR, of BRR, and of selected analogs, we investigated the association with the Wnt/β-catenin signaling and Hippo pathways.…”

Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer

“…Combined with nanotechnology, 9-O-octadecyl substituted BBR derivative induce mitochondrial apoptosis ( Song et al, 2019a ). 13-dichlorophenylalkyl BBR semisynthetic derivatives, especially 13-[3-(2,4-dichlorophenyl)propyl]-9,10-dimethoxy-5,6-dihy-drobenzo[ g ]-1,3benzodioxolo[5,6-a]quinolizinium chloride induced apoptosis in breast cancer cells, while, 13-[2-(4-chlorophenyl)ethyl]berberine iodide (NAX014) reduced HER2 overexpressing breast cancer cell migration, and intragastric administration of 20 mg/kg NAX014 in HER2/neu transgenic mice delayed the onset of mammary tumors with no negative effects on health and survival ( Pierpaoli et al, 2018 ; Pierpaoli et al, 2021 ).13-Ethylberberine induces apoptosis through the mitochondria-related apoptotic pathway in radiotherapy-resistant breast cancer cells ( Jin et al, 2019 ). 9-/13-lipophilic substituted BBR derivatives, such as 9-O-dodecyl-BBR, 13-dodecyl-BBR, and 13-O-dodecyl-BBR, show significant photocytotoxic effects on HepG2 cells and induce remarkable cancer cell apoptosis ( Lin et al, 2020 ).…”

Editorial for the Special Issue “New Drugs for Breast Cancer Treatment”

“…In particular, the readers of this Special Issue will learn about the anti-tumor activity of neosynthesized, natural, and already-available drugs that could be used as new anti-BC drugs. Indeed, the contributing authors have reported the antiproliferative activity of berberine and troglitazone derivatives, resveratrol analogs, atoquavone, clotrimazole, fenticonazole, compounds specifically targeting mitochondrial activity, and valproic acid, as well as NAMPT and carbonic anhydrase IX inhibitors [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”