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Updated: May 30, 2026
Method for Novel Anti-Cancer Drug Development using Tumor Explants of Surgical Specimens
Published on: July 29, 2011
Knockdown of the potential cancer stem-like cell marker Rex-1 improves chemotherapeutic effects in gliomas
Bong-Sun Kim1, Kyung-Sun Kang, Jee-In Choi
1Laboratory of Stem Cell Biology, Department of Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea.
Abstract:
In the present study, we show that Rex-1 mRNA and protein are found at high levels in both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioma cell subpopulations and malignant glioblastoma multiforme (GBM) tissue. We used a combination therapy of small interfering RNA (siRNA) against Rex-1 (siRex-1) and BCNU to target GBM cells. Rex-1 siRNA/BCNU treatment resulted in growth inhibition and a diminished S phase. The treatment efficiently induced P38/JNK and Akt/PI3K/GSK3β signaling and led to apoptosis both in vitro and in vivo. We also show that Rex-1/ABCG2 (ATP binding cassette transporter G2)-coexpressing subpopulations were chemoresistant; however, BCNU was not a substrate for ABCG2. siRex-1 treatment led to cell death in GBM subpopulations by promoting apoptosis. Moreover, siRex-1/BCNU combination therapy targeted both the major population and cancer stem cell-like subpopulations. Our findings are important for the development of clinical applications to treat GBM.
Insights
Targeting Rex-1 with siRNA and BCNU chemotherapy inhibits glioblastoma multiforme (GBM) growth by inducing apoptosis. This combination therapy effectively targets both major GBM cells and cancer stem cell-like subpopulations, offering new clinical applications.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- Drug resistance, particularly to chemotherapy agents like 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), is a major challenge in GBM treatment.
- Rex-1 expression is elevated in BCNU-resistant glioma cells and GBM tissues.
Purpose of the Study:
- To investigate the role of Rex-1 in GBM chemoresistance.
- To evaluate the efficacy of a combination therapy using small interfering RNA against Rex-1 (siRex-1) and BCNU in GBM.
- To explore the molecular mechanisms underlying the therapeutic effects.
Main Methods:
- Utilized Rex-1 siRNA (siRex-1) in combination with BCNU treatment on GBM cell lines and in vivo models.
- Assessed cell growth, cell cycle progression (S phase), apoptosis, and key signaling pathways (P38/JNK, Akt/PI3K/GSK3β).
- Investigated the co-expression of Rex-1 and ABCG2 (ATP binding cassette transporter G2) and BCNU's substrate status for ABCG2.
Main Results:
- siRex-1/BCNU combination therapy significantly inhibited GBM cell growth and reduced the S phase population.
- The treatment induced apoptosis and activated P38/JNK and Akt/PI3K/GSK3β signaling pathways.
- siRex-1 treatment alone induced cell death in GBM subpopulations, and the combination therapy effectively targeted both major GBM cells and cancer stem cell-like subpopulations.
Conclusions:
- Rex-1 plays a crucial role in GBM chemoresistance.
- Combination therapy with siRex-1 and BCNU is a promising strategy for overcoming BCNU resistance in GBM.
- This approach demonstrates potential for clinical applications in treating GBM, including targeting cancer stem cells.
