Dendrosomal curcumin significantly suppresses cancer cell proliferation in vitro and in vivo

https://doi.org/10.1016/j.intimp.2011.11.015Get rights and content

Abstract

Curcumin, the main compound of spice turmeric, is one of the natural products that has been shown to possess effective anti-cancer properties. However, the absorption efficacy of curcumin is too low to make dramatic results in therapy. Therefore, we based the main aim of this study on improving the bioavailability of curcumin taking advantage of dendrosome nanoparticles; and subsequently evaluating in vitro and in vivo anti-tumor properties of dendrosomal curcumin. In vitro studies were carried out utilizing A431 and WEHI-164 cell lines and mouse embryonic normal fibroblasts. Our data revealed that dendrosomal curcumin not only exhibits a much higher bioavailability than void curcumin (P < 0.05) but also inhibits the proliferation of cancer cells (P < 0.01) in a time- and dose-dependent manner that could be ascribed to the induction of apoptosis. However, dendrosome did not indicate any toxic effect on different types of cell lines. For in vivo studies, BALB/c tumor-bearing mice were treated with dendrosomal curcumin, void curcumin, dendrosome and PBS. The results indicated that dendrosomal curcumin reduces significantly the tumor size in comparison with void curcumin and control samples (P < 0.05). Furthermore, in animals treated with dendrosomal curcumin a longer survival was observed (P < 0.01). We also found that the mice treated with dendrosomal curcumin, showed a significant increase in splenocyte proliferation and IFN-γ production as well as a significant decrease in IL-4 production. This can be a proof of anti-tumor immunity caused by dendrosomal curcumin. The findings demonstrate that dendrosomal curcumin offers a great potential to be a promising anti-cancer therapeutic agent.

Highlights

► In this study we used dendrosomes to improve the bioavailability of curcumin. ► Dendrosomal curcumin significantly effects cancer cells rather than normal ones. ► Dendrosomal curcumin suppresses tumor growth in vivo. ► This effect is coupled with the induction of immune response.

Introduction

Cancer is defined as an intricate progressive multistep disease resulting from deregulation of several genes in different cellular pathways that lead to transformation of normal cells to malignant ones. Despite recent intensive attempts in understanding the molecular basis of tumor cells as well as successful targeted therapies for a limited number of tumor types, cancer remains to be one of the main causes of death worldwide [1]. On the basis of this idea and numerous epidemiological findings that diet plays a major role in cancer prevention, recent efforts have focused on traditional medicine (e.g. spices used in dietary) as a rich source of effective phytochemicals and their potential profits in treatment of chronic diseases especially cancer [1], [2]. Curcumin is the flavoring agent of turmeric powder (Curcuma longa) with various therapeutic properties especially anti-tumor activity without any side effects on normal cells [3]. Its anti-tumor activities embrace cancer growth inhibition and apoptosis induction by modulating different signal transduction pathways in vitro and in vivo [4]. In spite of these tempting attributes of curcumin, insolubility of the compound in aqueous solutions, actually the main reason for its poor bioavailability in vivo, has limited its exploitation as therapeutic agent [5]. To overcome this problem and increase the solubility of curcumin, numerous approaches have been taken by using adjuvants, liposomes and more recently nanoparticles [6], [7], [8], [9]. However, there has not been found any perfect formulation yet.

Here, we improved the solubility of curcumin thereby its anti-cancerous property by employing dendrosome nanoparticles in vitro and in vivo. Dendrosome is a neutral, amphipathic and biodegradable nano-material synthesized previously by our group and its capability has been shown in safely delivering genes into different cell lines [10], [11]. Our data for the first time reveals that dendrosome not only boosts the solubility of curcumin and its uptake in cell lines but also increases its toxicity on cancer cells rather than healthy ones. Meanwhile, our in vivo work with fibrosarcoma models in BALB/c mice suggests that dendrosomal curcumin compound suppresses tumor growth, coupled with induction of immune response against cancer cells.

Section snippets

Cells and reagents

Three cell lines including BALB/c mouse fibrosarcoma cell line WEHI-164, normal mouse embryonic fibroblast cell line MEF (both from Pasteur Institute, Tehran, Iran) and human epidermoidzcarcinoma cell line A431 (ATCC-Nr. CRL-1255) were grown in Dulbecco's modified Eagle's medium (DMEM; GIBCO, USA) containing 10% fetal bovine serum (FBS; GIBCO, USA) at 37 °C in a humidified atmosphere of 5% CO2. Curcumin was purchased from Sigma-Aldrich Company, USA. Dendrosome nanoparticle specified Den O400, a

Uptake kinetics of dendrosomal curcumin

Dendrosomal curcumin and void curcumin were dispersed in PBS. Fig. 1A indicates that dendrosomal curcumin was stably dispersed even after 24 h while curcumin powder began precipitating 1 h after dispersion and the pellet was clearly seen one day later. The homogenized feature of curcumin in dendrosomal curcumin configuration could be viewed by light and U.V. microscopy in Fig. 1B, but void curcumin aggregates as crystal bodies with different sizes. Also, the absorbance spectrum of dendrosomal

Discussion

The previous reports have proven that the solubility of curcumin could be enhanced while being solved or encapsulated in some drug porters [5], Thus, we hypothesized that the amphipathic nanoparticles of dendrosome O400 could improve the bioavailability of curcumin thereby escalating its anti-tumor effect. To document this idea, we employed two cancerous cell lines in vitro as well as BALB/c mouse model of fibrosarcoma tumor in vivo to analyze the anti-cancerous activity of dendrosomal curcumin

Acknowledgements

This work is dedicated to the memory of Dr. Prof. Mohammad Nabi Sarbolouki who first constructed dendrosome and presented them to the scientific community. We are deeply grateful to Tarbiat Modares University for funding this research. Also, the authors would like to thank Biomaterials Research Center (BRC) of Tehran University for helpful discussions and Dr. Prof. Barbara Krammer, head of Tumor Biology Department at the University of Salzburg, Austria who assisted us in performing the

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