Drugs that modify cholesterol metabolism alter the p38/JNK-mediated targeted and nontargeted response to alpha and Auger radioimmunotherapy

For the development of new anti-cancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution not only of targeted effects in irradiated cells, but also of off-target effects in non-irradiated neighboring cells because they affect the therapeutic efficacy and side effects. Here, we found that off-target cytotoxic and genotoxic effects occur in vitro (cultured cancer cells) and in vivo (xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT). Between 67 and 94% (alpha RIT) and 15 and 8% (Auger RIT) of cancer cells were killed by targeted effects, whereas between 7 and 36% (alpha RIT) and 27 and 29% (Auger RIT) of cells were killed by off-target effects. We then demonstrated that the off-target cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and c-JUN N-terminal kinases (JNK). Reactive oxygen species also played a significant role in these off-target 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 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 pravastatin inhibitory effect on Auger RIT. In conclusion, cell membrane-mediated off-target effects play a significant role during Auger and alpha RIT and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.

LADJOHOUNLOU Riad;  LOZZA Catherine;  PICHARD Alexandre;  CONSTANZO Julie;  KARAM Jihad;  LE FUR Pierre;  DESHAYES Emmanuel;  BOUDOUSQ Vincent;  PAILLAS Salome;  BUSSON Muriel;  LE BLAY Marion;  JARLIER Marta;  MARCATILI Sara;  BARDIÈS M;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  TORGUE Julien;  NAVARRO-TEULON Isabelle;  POUGET Jean-Pierre; 

2019-10-03

AMER ASSOC CANCER RESEARCH

JRC113164

1078-0432 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC113164,   

10.1158/1078-0432.CCR-18-3295 (online),