title: Vitamin B6 metabolism influences the intracellular accumulation of cisplatin.
abstract: Vitamin B6 metabolism influences the adaptive response of non-small lung carcinoma (NSCLC) cells to distinct, potentially lethal perturbations in homeostasis, encompassing nutrient deprivation, hyperthermia, hypoxia, irradiation as well as the exposure to cytotoxic chemicals, including the DNA-damaging agent cisplatin (CDDP). Thus, the siRNA-mediated downregulation of pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6, protects NSCLC cells (as well as a large collection of human and murine malignant cells of distinct histological derivation) from the cytotoxic effects of CDDP. Accordingly, the administration of pyridoxine, one of the inactive precursors of vitamin B6, exacerbates cisplatin-induced cell death, in vitro and in vivo, but only when PDXK is expressed. Conversely, antioxidants such as non-oxidized glutathione (GSH) are known to protect cancer cells from CDDP toxicity. Pyridoxine increases the amount of CDDP-DNA adducts formed upon the exposure of NSCLC cells to CDDP and aggravates the consequent DNA damage response. On the contrary, in the presence of GSH, NSCLC cells exhibit near-to-undetectable levels of CDDP-DNA adducts and a small fraction of the cell population activates the DNA damage response. We therefore wondered whether vitamin B6 metabolism and GSH might interact with CDDP in a pharmacokinetic fashion. In this short communication, we demonstrate that GSH inhibits the intracellular accumulation of CDDP, while pyridoxine potentiates it in a PDXK-dependent fashion. Importantly, such pharmacokinetic effects do not involve plasma membrane transporters that mediate a prominent fraction of CDDP influx, i.e., solute carrier family 31, member 1 (SLC31A1, best known as copper transporter 1, CTR1) and efflux, i.e., ATPase, Cu ( 2+)  transporting, β polypeptide (ATP7B).
authors.affiliation: Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Marsili
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.forename: Judith
authors.initials: J
authors.lastname: Michels
authors.forename: Pauline
authors.initials: P
authors.lastname: Garcia
authors.forename: Erika
authors.initials: E
authors.lastname: Vacchelli
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism* / Q000494:pharmacology; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D011731:Pyridoxal Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D025101:Vitamin B 6 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D034741:RNA, Small Interfering; C490079:SLC31A1 protein, human; D025101:Vitamin B 6; D011731:Pyridoxal Kinase; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D005978:Glutathione; D002945:Cisplatin
keywords: A549; N-acetyl-cysteine; PDXP; Wilson disease; apoptosis; reactive oxygen species