Vitamin B6 metabolism influences the intracellular accumulation of cisplatin

Lorenzo Galluzzi, Sabrina Marsili, Ilio Vitale, Laura Senovilla, Judith Michels, Pauline Garcia, Erika Vacchelli, Etienne Chatelut, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticle

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 PDXKdependent 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., ATP ase, Cu2+ transporting, β polypeptide (ATP 7B).

Original languageEnglish
Pages (from-to)417-421
Number of pages5
JournalCell Cycle
Volume12
Issue number3
DOIs
Publication statusPublished - Feb 1 2013

Keywords

  • A549
  • Apoptosis
  • N-acetyl-cysteine
  • PDXP
  • Reactive oxygen species
  • Wilson disease

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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  • Cite this

    Galluzzi, L., Marsili, S., Vitale, I., Senovilla, L., Michels, J., Garcia, P., Vacchelli, E., Chatelut, E., Castedo, M., & Kroemer, G. (2013). Vitamin B6 metabolism influences the intracellular accumulation of cisplatin. Cell Cycle, 12(3), 417-421. https://doi.org/10.4161/cc.23275