Protective effects of dendrosomal curcumin on an animal metastatic breast tumor

Abstract

Curcumin has been shown to inhibit migration and invasion of cancer angiogenesis via interacting with key regulatory molecules like NF-κB. Rapidly metabolized and conjugated in the liver, curcumin has the limited systemic bioavailability. Previous results have shown a new light of potential biocompatibility, biodegradability, as well as anti-cancer effects of dendrosomal curcumin (DNC) in biological systems. The present study aims to deliberate the protective effects of DNC on metastatic breast tumor in vitro and in vivo. After the dosing procedure, twenty-seven female mice were divided into 40 and 80 mg/kg groups of DNC, along with a control group to investigate the anti-metastatic effects of DNC on mammary tumor-bearing mice. In vitro results showed that the different concentrations of DNC reduced the migration and the adhesion of 4T1 cells after 24 h (P<0.05). Under the dosing procedure, DNC was safe at 80 mg/kg and lower doses. The treated DNC animals had a higher survival rate and lower metastatic signs (14%) compared to control (100%) (P<0.05). The metastatic tumors were more common in control mice than the treated groups in the lung, the liver and the sternum tissues. Animals treated with DNC had smaller tumor volume in comparison with control group (P<0.05). Final mean tumor volume reached to approximately 1.11, 0.31 and 0.27 cm³ in the control, and 40 and 80 mg/kg DNC groups, respectively (P<0.05). Furthermore, suppression of NF-κB expression by DNC led to down-regulation of VEGF, COX-2, and MMP-9 expressions in the breast tumor, the lung, the brain, the spleen and the liver tissues (P<0.05). These outcomes indicate that dendrosomal curcumin has a chemoprotective effect on the breast cancer metastasis through suppression of NF-κB and its regulated gene products.

Introduction

Metastasis is a multi-step process involving complex interactions between the disseminating cancer cells, and their microenvironment (Alizadeh et al., 2014). Cancer metastasis is the cause of 90% of all deaths from cancer and exhibits an outstandingly different situation of clinical characteristics (Khan and Mukhtar, 2010), therefore, agents that inhibit metastasis provide a major advantage in treating cancers. Most tumors activate the transcription factor nuclear factor-kB (NF-kB), whereas natural chemopreventive agents suppress it, indicating a strong link between the tumor biology and the anti-cancer effects of various natural compounds (Luo et al., 2005). Experimental evidence has suggested that NF-κB has an important role not only in cancer initiation but also in cancer progression and metastasis (Huber et al., 2004). NF-κB regulates the genes expression involved in cancer metastasis such as MMPs, VEGF and COX-2 (Xie et al., 2010). NF-κB has also been described as a major culprit in cancer because it is constitutively activated in most human cancers, especially in the poorly differentiated cancers like those pertaining to the breasts (Bharti and Aggarwal, 2002). Several studies have shown that curcumin inhibits cancer angiogenesis, specifically migration and invasion through interacting with the key regulatory molecules like NF-κB (Himelstein et al., 1993).

Curcumin is a lipid-soluble compound extracted from the plant Curcuma Longa, and can potentially prevent cancer development with no discernible toxicity (Kelloff et al., 2000, Aggarwal et al., 2007). It is cost-effective, and has been used for centuries without known side-effects (Shishodia et al., 2005). However, absorption, distribution, metabolism and excretory studies of curcumin in recent years focused on its low bioavailability in systemic circulation (Ghalandarlaki et al., 2014). Subsequently, many methods were tested to overcome this defect like the use of the dendrosomal curcumin (DNC) (Sarbolouki et al., 2000, Alizadeh et al., 2012). Our previous results shed a new light on the potential biocompatibility, the biodegradability and the anticancer effects of DNC in the biological systems (Alizadeh et al., 2012, Babaei et al., 2012, Sarbolouki et al., 2012, Khaniki et al., 2013, Alizadeh et al., 2015, Mirgani et al., 2014). Accordingly, the present study has been designed to investigate the protective effects of DNC on the metastatic breast cancer cell line, and the model metastatic of mouse mammary tumor-bearing.