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

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.

Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma

“…It could also be related to the enhancement of immunogenicity by radiation, as we already demonstrated for the B16F10 melanoma model [53], also consistent with the increased expression of inflammatory genes shown by transcriptomics. Additional studies need to be conducted to confirm that these pathways are involved in the NRAS Q61K 1007 response to [ 131 I]ICF01012-TRT, as modified lipid metabolism has already been reported to alter the efficiency of radioimmunotherapy [54]. In previous studies, we showed that TRT reduces hematogenous dissemination, especially lung invasion [21], by modifying pseudoepithelial-mesenchymal transition pEMT-mechanisms [24].…”

Modulation of Plasma Membrane Composition and Microdomain Organization Impairs Heat Shock Protein Expression in B16-F10 Mouse Melanoma Cells

“…For example, both JNK [33] and p38 MAP kinases [34] were previously suggested to take part in membrane-associated HSP25 induction. Of note, cholesterol depletion inhibited JNK and p38 MAP kinase-associated signaling in different model systems [35,36]. Thus, it is tempting to speculate that MβCD-or nystatin-induced PM modifications impair different signaling cascades towards HSF1 resulting in an altered PTM profile.…”

Ceramide-Enriched Membrane Domains Contribute to Targeted and Nontargeted Effects of Radiation through Modulation of PI3K/AKT Signaling in HNSCC Cells

“…To determine the contribution of targeted and nontargeted effects, we used a Bliss independence mathematical model [ 22 , 56 ]. It is essential to notice that donor cells are, in reality, at the same time donor and recipient cells (i.e., irradiated cells secrete substances toward neighboring irradiated cells).…”

“…The precise nature of factors that mediate the nontargeted effect is unknown, but reactive oxygen and nitrogen species (ROS/RNS) and various cytokines have been involved [ 17 , 18 , 19 ]. Other studies [ 20 , 21 , 22 ] have also demonstrated the involvement of plasma membrane signaling in the bystander effect via the generation of ceramide (considered as a mediator of radiation), leading to activation of the mitogen-activated protein kinases (MAPK) and other pathways, which then transduce amplified signals into the nucleus.…”