title: 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.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Iovine
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Oliviero
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Garofalo
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Orefice
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nocella
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Borbone
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Piccialli
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Centore
authors.affiliation: Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, Leuven, Belgium; Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Piccialli
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Maria Assunta
authors.initials: MA
authors.lastname: Bevilacqua
mesh_terms: D002336:Carnosine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D002336:Carnosine