The Anti-Proliferative Effect of L-Carnosine Correlates with a Decreased Expression of Hypoxia Inducible Factor 1 alpha in Human Colon Cancer Cells

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.

Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

“…We demonstrate in this study that carnosine reduces IGFBP1 in diabetes by a complex mechanism involving also a direct decrease of HIF stability and function. This is in agreement with a recent study that found a destabilizing effect of carnosine on HIF-1a in a cancer cell line (HCT-116) (Iovine et al 2014). Furthermore, in a mouse model of retina ischemia it has been shown that carnosine treatment decrease HIF-1a at the protein level after 6 h ischemia (Ji et al 2014).…”

Regulating Effect Of Carnosine And /Or L- Arginine On The Expression Of Inflammatory Molecules Induced Nephropathy In The Hypoxic Rat Model

“…The ability of carnosine and /or arginine to suppress the production of HIF-1α may correlate to their anti-inflammatory and anti-oxidant roles. Previous study found that carnosine could reduce the HIF-1α stability and induced its proteasome degradation (Iovine et al 2014). On the other hand, carnosine could act on HIF-1α signaling, decreasing its protein level and consequently its transcriptional activity (Iovine et al 2014).…”

Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity

“…The role of L-carnosine in the complex was to enhance anticancer effect when combined with oncolytic adenovirus. We hypothesized that combined agents could exhibit synergistic anticancer properties, as it is known that oncolytic adenovirus are novel antitumor agents with the ability to selectively replicate and lyse tumor cells while remaining innocuous to the rest of the body (7) and L-carnosine alone has antiproliferative cancer effect (3). Indeed, we found that the complex formed by the interaction between L-carnosine and adenovirus was able to induce apoptosis and necrosis at significantly lower concentration of L-carnosine compared with that required for the drug alone.…”

“…The natural antioxidant dipeptide L-carnosine belongs to this class of molecules because it has been proven to have a significant anticancer activity both in vitro and in vivo (3). A number of biologic functions have been recognized to this molecule, including antioxidant activity, ability to chelate metal ions, inhibition of protein glycosylation, anti-inflammatory, and antisenescence properties (4).…”