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

Abstract

In this study, we sought to determine how intragastric (IG) administration of the NAX014 compound at a dose of 20 mg/kg would affect the safety, antitumor, and antimetastatic activities as measured by the kinetics of the development of spontaneous lung metastases and mammary tumours in HER-2/neu transgenic mice. It has been demonstrated that the natural isoquinoline alkaloid Berberine (BBR) has a number of therapeutic properties, including anticancer activity. It has been designed and synthesised to create various BBR derivatives in order to create new substances with improved 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. The present study showed that IG NAX014 administration (i) delays the development of spontaneous mammary tumors in HER-2/neu transgenic mice without negative effects on health and survival; (ii) inhibits breast cancer cell migration and metastasis in vitro and in vivo; (iii) induces in vitro and in vivo tumor cells senescence; and (iv) decreases TNF-\(\alpha\) and VEGF plasma levels. Despite the fact that NAX014 had no effect on tumor-infiltrating lymphocytes, it was discovered that mice treated with NAX014 had lower levels of circulating TNF- and VEGF. The NAX014 compound is discussed in the context of the overall findings as a potential tool for therapeutic approaches against breast cancers that overexpress HER-2.