Fingolimod Augments Monomethylfumarate Killing of GBM Cells
Authors: Andrew Poklepovic
Laurence Booth
John F Hancock
Paul Dent
Jane L Roberts
Journal: Frontiers in Oncology (2020)
Discipline: CLINICAL MEDICINE
Keywords: Gilenya; RAS; Tecfidera; dimethyl fumarate; fingolimod
Affiliations: Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, United States., Departments of Medicine, Virginia Commonwealth University, Richmond, VA, United States., Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, United States.

Abstract:  Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells. 

Retracted: No

PubPeer comments:
 In Figure 7c, microscopy data has been duplicated and presented as something else. ![file] , 
 As a reminder, some background is available in the discussion here: https: pubpeer.com publications 44B6D474252DFE3DB80F01B555C4E7 , 
 April 2020 A Corrigendum on Fingolimod Augments Monomethylfumarate Killing of GBM Cells by Dent, P., Booth, L., Roberts, J. L., Poklepovic, A., and Hancock, J. F. (2020). Front. Oncol. 10:22. doi: 10.3389 fonc.2020.00022 In the original article, there was a mistake in Figure 7C as published. By error, the image for FAS-L treated with MMF was included twice; once correctly and once as FAS-L treated with vehicle control. The corrected Figure 7C for FAS-L assessments appears below. FIGURE 7 ![file] The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. ,