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Published on: October 27, 2014
Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA
Jin-Chul Heo1, Tae-Hoon Jung1,2, Sungjin Lee1
1Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
Abstract:
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.
Insights
Bexarotene, a retinoid X receptor agonist, effectively induces glioblastoma cell differentiation, inhibiting tumor growth and migration. It offers a safer alternative to ATRA by minimizing adverse transglutaminase 2 effects.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor.
- Cell differentiation can inhibit tumor growth.
- Identifying novel differentiation agents is crucial for GBM treatment.
Purpose of the Study:
- To screen for drugs that induce morphological differentiation in GBM cells.
- To evaluate bexarotene as a potential GBM differentiation agent.
- To compare bexarotene's efficacy and safety with all-trans retinoic acid (ATRA).
Main Methods:
- Image-based phenotypic screening of GBM cells.
- Assessing neurospheroidal colony formation and cell migration.
- Analyzing gene expression (nestin, GFAP, KLF9, RGS4, GDF15, ANGPTL4, CXCR4) and transglutaminase 2 (TG2) activity.
- Evaluating in vivo efficacy in a GBM xenograft mouse model.
Main Results:
- Bexarotene significantly inhibited GBM cell colony formation and migration.
- Bexarotene treatment altered gene expression, reducing nestin and increasing GFAP.
- Compared to ATRA, bexarotene showed weaker TG2 induction, a marker of drug resistance.
Conclusions:
- Bexarotene demonstrates potent differentiation-inducing effects in GBM cells.
- Bexarotene exhibits promising anti-tumor activity in vitro and in vivo.
- Bexarotene represents a potentially more beneficial differentiation agent than ATRA for GBM treatment due to a more favorable safety profile regarding TG2 induction.
