Abstract
In recent years considerable attention has been given to the use of natural substances as anticancer drugs. The natural antioxidant dipeptide L-carnosine belongs to this class of molecules because it has been proved to have a significant anticancer activity both in vitro and in vivo. Previous studies have shown that L-carnosine inhibits the proliferation of human colorectal carcinoma cells by affecting the ATP and Reactive Oxygen Species (ROS) production. In the present study we identified the Hypoxia-Inducible Factor 1α (HIF-1α) as a possible target of L-carnosine in HCT-116 cell line. HIF-1α protein is over-expressed in multiple types of human cancer and is the major cause of resistance to drugs and radiation in solid tumours. Of particular interest are experimental data supporting the concept that generation of ROS provides a redox signal for HIF-1α induction, and it is known that some antioxidants are able to suppress tumorigenesis by inhibiting HIF-1α. In the current study we found that L-carnosine reduces the HIF-1α protein level affecting its stability and decreases the HIF-1 transcriptional activity. In addition, we demonstrated that L-carnosine is involved in ubiquitin-proteasome system promoting HIF-1α degradation. Finally, we compared the antioxidant activity of L-carnosine with that of two synthetic anti-oxidant bis-diaminotriazoles (namely 1 and 2, respectively). Despite these three compounds have the same ability in reducing intracellular ROS, 1 and 2 are more potent scavengers and have no effect on HIF-1α expression and cancer cell proliferation. These findings suggest that an analysis of L-carnosine antioxidant pathway will clarify the mechanism underlying the anti-proliferative effects of this dipeptide on colon cancer cells. However, although the molecular mechanism by which L-carnosine down regulates or inhibits the HIF-1α activity has not been yet elucidated, this ability may be promising in treating hypoxia-related diseases.
Highlights
L-Carnosine (b-Ala-His) is a naturally occurring histidine dipeptide, endogenously synthesized and widely found in the brain, muscle, kidney, stomach, and, in large amounts, in the skeletal muscle
We evaluated the effect of L-carnosine treatment on Hypoxia-Inducible Factor 1a (HIF-1a) activity in human colon cancer cells
We previously demonstrated that L-carnosine could abate Reactive Oxygen Species (ROS) induced by the KRAS oncogene as well as the production of ATP [2]
Summary
L-Carnosine (b-Ala-His) is a naturally occurring histidine dipeptide, endogenously synthesized and widely found in the brain, muscle, kidney, stomach, and, in large amounts, in the skeletal muscle This dipeptide has been proved to perform a number of biological functions, including anti-oxidant activity, ability to chelate metal ions, inhibition of protein glycosylation, anti-inflammatory and anti-senescence properties [1]. To understand the mechanisms responsible for the L-carnosine effect we have examined how this dipeptide affects ROS intracellular levels in comparison with two new anti-oxidant bis-diaminotriazole compounds (namely 1 and 2 respectively) available from our laboratories and whose antioxidant activity is unpublished Despite these three compounds have the same ability in reducing intracellular ROS, we found that 1 and 2 have no effect on HIF-1a expression and cancer cell proliferation. We conclude that an analysis of the L-carnosine antioxidant pathway will clarify the mechanism underlying the effects of this dipeptide on colon cancer cells
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