title: l-carnosine dipeptide overcomes acquired resistance to 5-fluorouracil in HT29 human colon cancer cells via downregulation of HIF1-alpha and induction of apoptosis.
abstract: Hypoxia-inducible factor (HIF-1α) protein is over-expressed in many human cancers and is a major cause of resistance to drugs. HIF-1α up-regulation decreases the effectiveness of several anticancer agents, including 5-fluorouracil (5-FU), because it induces the expression of drug efflux transporters, alters DNA repair mechanisms and modifies the balance between pro- and antiapoptotic factors. These findings suggest that inhibition of HIF-1α activity may sensitize cancer cells to cytotoxic drugs. We previously reported that l-carnosine reduces HIF-1α expression by inhibiting the proliferation of colon cancer cells. In the present study we investigated the effect of l-carnosine on HT29 colon cancer cells with acquired resistance to 5-FU. We found that l-carnosine reduces colon cancer cell viability, decreases HIF-1α and multi-drug resistant protein MDR1-pg expression, and induces apoptosis. Moreover, the l-carnosine/5-FU combination lowers the expression of some chemoresistance markers. The combination index evaluated in vitro on the HT29-5FU cell line by median drug effect analysis reveals a significant synergistic effect.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, via Sergio Pansini 5, 80131 Napoli, Italy. Electronic address: barbara.iovine@unina.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Iovine
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, via Sergio Pansini 5, 80131 Napoli, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guardia
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Irace
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, via Sergio Pansini 5, 80131 Napoli, Italy.
authors.forename: Maria Assunta
authors.initials: MA
authors.lastname: Bevilacqua
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002336:Carnosine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002336:Carnosine; D005472:Fluorouracil
keywords: 5-Fluorouracil; Apoptosis; Chemoresistance; Hypoxia-inducible factor-1; Multi-drug resistance; l-carnosine