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Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy

Riad Ladjohounlou 1 Catherine Lozza 1 Alexandre Pichard 1 Julie Constanzo 1 Jihad Karam 1 Pierre Le Fur 1 Emmanuel Deshayes 1 Vincent Boudousq 1 Salomé Paillas 1 Muriel Busson 1 Marion Le Blay 1 Marta Jarlier 2 Sara Marcatili 3 Manuel Bardiès 3 Frank Bruchertseifer 4 Alfred Morgenstern 4 Julien Torgue 5 Isabelle Navarro-Teulon 1 Jean-Pierre Pouget 1
1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
2 ICM - Institut du Cancer de Montpellier
3 CRCT - Centre de Recherches en Cancérologie de Toulouse
4 Directorate for Nuclear Safety & Security - European Commission - Joint Research Centre [Karlsruhe, Germany]
5 ORANO Med [Plano, TX, USA]
Abstract : Purpose: For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects. Experimental Design: Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects in vitro and in vivo (in xenografted mice) during alpha (212 Pb/ 212 Bi, 213 Bi) and Auger (125 I) radioimmunotherapy (RIT). Results: Between 67% and 94% (alpha RIT) and 8% and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-kB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT. Conclusions: Cell membrane-mediated nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.
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https://www.hal.inserm.fr/inserm-03024631
Contributor : Jean-Pierre Pouget <>
Submitted on : Wednesday, November 25, 2020 - 10:01:56 PM
Last modification on : Friday, November 27, 2020 - 3:25:20 AM
Long-term archiving on: : Friday, February 26, 2021 - 8:30:49 PM

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INSERM | UNIV-TLSE3 | VALDAURELLE | FNCLCC | UNIV-MONTPELLIER | IRCM | CNRS | BS

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Riad Ladjohounlou, Catherine Lozza, Alexandre Pichard, Julie Constanzo, Jihad Karam, et al.. Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy. Clinical Cancer Research, American Association for Cancer Research, 2019, 25 (15), pp.4775-4790. ⟨10.1158/1078-0432.CCR-18-3295⟩. ⟨inserm-03024631⟩

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