American Association for Cancer Research
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10780432ccr183295-sup-210135_2_supp_5463223_pq4cr8.png (106.97 kB)

Figure S8 from Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy

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posted on 2023-03-31, 21:47 authored by Riad Ladjohounlou, Catherine Lozza, Alexandre Pichard, Julie Constanzo, Jihad Karam, Pierre Le Fur, Emmanuel Deshayes, Vincent Boudousq, Salomé Paillas, Muriel Busson, Marion Le Blay, Marta Jarlier, Sara Marcatili, Manuel Bardiès, Frank Bruchertseifer, Alfred Morgenstern, Julien Torgue, Isabelle Navarro-Teulon, Jean-Pierre Pouget

SUPPLEMENTARY FIG. S8. In vivo effects of MBCD on tumor growth in mice treated with low activities of 213Bi-anti-MISRII mAb.

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ORANO Med LLC

SIRIC Montpellier

Ligue Nationale Contre le Cancer

Action Nu 1.1 of Plan Cancer 2009-2103

French National Research Agency

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ARTICLE ABSTRACT

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. Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects in vitro and in vivo (in xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT). 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-κB 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. 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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