title: Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer.
abstract: cis-Diamminedichloroplatinum(II) (CDDP), which is mostly referred to as cisplatin, is a widely used antineoplastic. The efficacy of cisplatin can be improved by combining it with the vitamin B6 precursor pyridoxine. Here, we evaluated the putative synergistic interaction of CDDP with pyridoxine in the treatment of an orthotopic mouse model of non-small-cell lung cancer (NSCLC). CDDP and pyridoxine exhibited hyperadditive therapeutic effects. However, this synergy was only observed in the context of an intact immune system and disappeared when the otherwise successful drug combination was applied to the same NSCLC cancer implanted in the lungs of athymic mice (which lack T lymphocytes). Immunocompetent mice that had been cured from NSCLC by the combined regimen of CDDP plus pyridoxine became resistant against subcutaneous rechallenge with the same (but not with an unrelated) cancer cell line. In vitro, CDDP and pyridoxine did not only cause synergistic killing of NSCLC cells but also elicited signs of immunogenic cell death including an endoplasmic reticulum stress response and exposure of calreticulin at the surface of the NSCLC cells. NSCLC cells treated with CDDP plus pyridoxine in vitro elicited a protective anticancer immune response upon their injection into immunocompetent mice. Altogether, these results suggest that the combined regimen of cisplatin plus pyridoxine mediates immune-dependent antineoplastic effects against NSCLC.
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France.
authors: F
authors: F
authors: Aranda
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France [4] Université Paris Sud, Villejuif, France.
authors: N
authors: N
authors: Bloy
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France.
authors: J
authors: J
authors: Pesquet
authors: INSERM U1030, Villejuif, France.
authors: B
authors: B
authors: Petit
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: K
authors: K
authors: Chaba
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France.
authors: A
authors: A
authors: Sauvat
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France.
authors: O
authors: O
authors: Kepp
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France.
authors: N
authors: N
authors: Khadra
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France.
authors: D
authors: D
authors: Enot
authors: Center for Systems Biology, Massachusetts General Hospital/Harvard Medical School, Pittet Lab, Boston, MA, USA.
authors: C
authors: C
authors: Pfirschke
authors: Center for Systems Biology, Massachusetts General Hospital/Harvard Medical School, Pittet Lab, Boston, MA, USA.
authors: M
authors: M
authors: Pittet
authors: 1] Université Paris Sud, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Centre d'Investigation Clinique Biothérapie CICBT 507, Villejuif, France.
authors: L
authors: L
authors: Zitvogel
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Cell Biology Platforms, Villejuif, France [4] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
authors: G
authors: G
authors: Kroemer
authors: 1] Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France [2] Metabolomics and Cell Biology Platforms, Villejuif, France [3] INSERM U1015, Villejuif, France.
authors: L
authors: L
authors: Senovilla
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D059865:Endoplasmic Reticulum Stress; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011736:Pyridoxine / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D037282:Calreticulin; D011736:Pyridoxine; D002945:Cisplatin