title: Alpha Particles Induce Autophagy in Multiple Myeloma Cells.
abstract: OBJECTIVE
  Radiation emitted by the radionuclides in radioimmunotherapy (RIT) approaches induce direct killing of the targeted cells as well as indirect killing through the bystander effect. Our research group is dedicated to the development of α-RIT, i.e., RIT using α-particles especially for the treatment of multiple myeloma (MM). γ-irradiation and β-irradiation have been shown to trigger apoptosis in tumor cells. Cell death mode induced by (213)Bi α-irradiation appears more controversial. We therefore decided to investigate the effects of (213)Bi on MM cell radiobiology, notably cell death mechanisms as well as tumor cell immunogenicity after irradiation.
  
  
  METHODS
  Murine 5T33 and human LP-1 MM cell lines were used to study the effects of such α-particles. We first examined the effects of (213)Bi on proliferation rate, double-strand DNA breaks, cell cycle, and cell death. Then, we investigated autophagy after (213)Bi irradiation. Finally, a coculture of dendritic cells (DCs) with irradiated tumor cells or their culture media was performed to test whether it would induce DC activation.
  
  
  RESULTS
  We showed that (213)Bi induces DNA double-strand breaks, cell cycle arrest, and autophagy in both cell lines, but we detected only slight levels of early apoptosis within the 120 h following irradiation in 5T33 and LP-1. Inhibition of autophagy prevented (213)Bi-induced inhibition of proliferation in LP-1 suggesting that this mechanism is involved in cell death after irradiation. We then assessed the immunogenicity of irradiated cells and found that irradiated LP-1 can activate DC through the secretion of soluble factor(s); however, no increase in membrane or extracellular expression of danger-associated molecular patterns was observed after irradiation.
  
  
  CONCLUSIONS
  This study demonstrates that (213)Bi induces mainly necrosis in MM cells, low levels of apoptosis, and autophagy that might be involved in tumor cell death.
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gorin
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gouard
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Ménager
authors.affiliation: Institute for Transuranium Elements , Karlsruhe , Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Institute for Transuranium Elements , Karlsruhe , Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France ; Nuclear Medicine Department, CHU Nantes , Nantes , France.
authors.forename: Alain
authors.initials: A
authors.lastname: Faivre-Chauvet
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Guilloux
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France ; Institut de Cancérologie de l'Ouest , Saint-Herblain , France.
authors.forename: Michel
authors.initials: M
authors.lastname: Chérel
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France.
authors.forename: François
authors.initials: F
authors.lastname: Davodeau
authors.affiliation: CRCNA - UMR 892 INSERM , Nantes , France ; 6299 CNRS , Nantes , France ; Université de Nantes , Nantes , France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Gaschet
keywords: autophagy; bismuth-213; immunogenicity; ionizing radiation; multiple myeloma; radiobiology