Carnosine retards tumor growth in vivo in an NIH3T3-HER2/neu mouse model

Christof Renner,Kathrin D Geiger,Matthias Hermes,Jürgen Meixensberger,Nadine Zemitzsch,Frank Gaunitz,Beate Fuchs,Rolf Gebhardt,Jan Hengstler

doi:10.1186/1476-4598-9-2

Abstract

BackgroundIt was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma. In the present work we investigated whether carnosine also affects tumor growth in vivo and may therefore be considered for human cancer therapy.ResultsA mouse model was used to investigate whether tumor growth in vivo can be inhibited by carnosine. Therefore, NIH3T3 fibroblasts, conditionally expressing the human epidermal growth factor receptor 2 (HER2/neu), were implanted into the dorsal skin of nude mice, and tumor growth in treated animals was compared to control mice. In two independent experiments nude mice that received tumor cells received a daily intra peritoneal injection of 500 μl of 1 M carnosine solution. Measurable tumors were detected 12 days after injection. Aggressive tumor growth in control animals, that received a daily intra peritoneal injection of NaCl solution started at day 16 whereas aggressive growth in mice treated with carnosine was delayed, starting around day 19. A significant effect of carnosine on tumor growth was observed up to day 24. Although carnosine was not able to completely prevent tumor growth, a microscopic examination of tumors revealed that those from carnosine treated animals had a significant lower number of mitosis (p < 0.0003) than untreated animals, confirming that carnosine affects proliferation in vivo.ConclusionAs a naturally occurring substance with a high potential to inhibit growth of malignant cells in vivo, carnosine should be considered as a potential anti-cancer drug. Further experiments should be performed in order to understand how carnosine acts at the molecular level.

Highlights

It was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma
Carnosine inhibits growth of NIH3T3-HER2/neu cells in culture Before the experiments with animals were initiated, it was asked, whether NIH3T3-HER2/neu cells are influenced by carnosine in culture, as demonstrated for cells from human glioblastoma [12]
This result is in good agreement with the previously published data from tumor cells derived from patients with malignant glioma and it encouraged to ask whether the effect of carnosine on tumor cell growth may be observable in vivo

Summary

Introduction

It was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma. A dipeptide discovered more than 100 years ago [1] is a naturally occurring substance synthesized by endogenous carnosine synthetase It is present in mammalian brain at a concentration between 0.7 and 2.0 mM [2] and reaches concentrations of up to 20 mM in skeletal muscle [3]. Not much is known about its physiological function but several possible roles have been considered since its first discovery (for detailed review see [4,5]) Among these functions ph-buffering [6], metal chelation [7] or neurotransmitter function [8] have been discussed and the currently most intensively debated aspects are its potential protective effect against oxidative stress [9], its likely role as a therapeutic agent for the treatment of Alzheimer’s disease [10] and its use termed neu or erbB-2, belongs to the epidermal growth factor receptors, involved in cell cycle control and cell differentiation. Tumor size of animals, receiving carnosine or NaCl as control, was determined daily

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