Regulation of dimethyl-fumarate toxicity by proteasome inhibitors

Area of Science:

• Neuro-oncology
• Cancer Biology
• Immunology

Background:

• Glioblastoma (GBM) remains a challenging cancer with limited treatment options.
• Dimethyl-fumarate (DMF) and its active metabolite mono-methyl-fumarate (MMF) are known for their immunomodulatory effects.
• The potential of MMF in combination cancer therapy requires further investigation.

Purpose of the Study:

• To investigate the biological effects of MMF, alone and in combination with other agents, on primary human glioblastoma (GBM) cells.
• To explore MMF's impact on GBM cell invasiveness, response to radiation, and interaction with immune cells.
• To elucidate the molecular mechanisms underlying MMF's anti-cancer activity.

Main Methods:

• Treatment of primary GBM cells, breast, and colon cancer cells with MMF and proteasome inhibitors (velcade, carfilzomib).
• Assessment of cell viability, invasiveness, and response to ionizing radiation and temozolomide.
• Analysis of cytokine production in activated microglia, and evaluation of drug combinations with Gilenya.
• Molecular studies involving gene/protein expression (c-FLIP-s, BCL-XL, CD95, FADD, AKT, ERK1/2, mTOR, ATG5, Beclin1), signaling pathways, ER stress response, and reactive oxygen species (ROS).

Main Results:

• MMF significantly enhanced the toxicity of velcade and carfilzomib in GBM, breast, and colon cancer cells.
• MMF reduced GBM cell invasiveness and increased the efficacy of ionizing radiation and temozolomide.
• MMF demonstrated direct toxicity to activated microglia, reducing pro-inflammatory cytokine production (IL-6, TGFβ, TNFα).
• Combination therapy with MMF and Gilenya further reduced GBM and microglia viability and cytokine levels.
• Molecular analyses revealed MMF's role in CD95/FADD-mediated apoptosis, inactivation of AKT/ERK/mTOR pathways, induction of autophagy, and ER stress.
• Inhibition of specific molecular pathways (AKT/ERK/mTOR, ER stress arms) and ROS production were critical for MMF's cytotoxic effects.

Conclusions:

• MMF exhibits potent anti-cancer properties against glioblastoma and other cancer types, both as a single agent and in combination therapies.
• MMF modulates the tumor microenvironment by affecting microglia and synergizing with established cancer treatments.
• The findings highlight MMF as a promising therapeutic agent for glioblastoma, with its efficacy linked to specific molecular pathways including apoptosis, autophagy, and ER stress.