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Updated: Mar 2, 2026
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Combination therapy with micellarized cyclopamine and temozolomide attenuate glioblastoma growth through Gli1
Yu-Jie Liu1, Ying-Cong Ma1, Wen-Jie Zhang1
1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
Abstract:
Glioblastoma multiforme (GBM) is the most common and deadly brain cancer, characterized by its aggressive proliferation to adjacent tissue and high recurrence rate. We studied the efficacy and related mechanisms of the combination of cyclopamine (Cyp, a Sonic-hedgehog pathway (Shh) inhibitor) and temozolomide (TMZ, the clinically most used chemotherapeutic agent) in anti-GBM treatment. The micellarized Cyp (MCyp) showed better performance than Cyp solution in inhibiting GBM cells proliferation (3.77-fold against U87 MG cells and 3.28-fold against DBTRG-05MG cells) and clonogenity (1.35-fold against U87 MG cells and 2.17-fold against DBTRG-05MG cells), and preferred behavior of inhibiting cell invasion, colony formation through attenuated Gli1 expression. In addition, combination of MCyp and TMZ exhibited synergistic cytotoxicity, correlating with their ability in inducing apoptosis and eliminating neurospheres formation, and the combination of TMZ was accompanied with the enhanced blockage of Shh pathway. The optimal ratio of MCyp combined to TMZ was 1:20. So we proposed to use TMZ to kill tumor parenchyma and MCyp as the cancer stem cells inhibitor to resist tumor recurrence. These findings demonstrated that combination of TMZ with micellarized Cyp is a promising strategy for exerting different functions of drugs for tumor treatment.
Insights
Combining micellarized cyclopamine (MCyp) with temozolomide (TMZ) shows promise for treating glioblastoma multiforme (GBM). This combination effectively inhibits GBM cell proliferation and recurrence by targeting cancer stem cells and tumor parenchyma.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain cancer with high recurrence rates.
- Current treatments face challenges due to tumor resistance and heterogeneity.
Purpose of the Study:
- To evaluate the efficacy of combining micellarized cyclopamine (MCyp), a Sonic-hedgehog pathway inhibitor, with temozolomide (TMZ) for GBM treatment.
- To elucidate the mechanisms underlying the synergistic effects of MCyp and TMZ.
Main Methods:
- In vitro assessment of MCyp and TMZ combination on GBM cell proliferation, invasion, and colony formation.
- Evaluation of apoptosis induction and neurosphere formation inhibition.
- Analysis of Sonic-hedgehog (Shh) pathway activity, specifically Gli1 expression.
Main Results:
- Micellarized Cyp (MCyp) demonstrated superior inhibition of GBM cell proliferation and clonogenicity compared to unconjugated cyclopamine.
- The combination of MCyp and TMZ exhibited synergistic cytotoxicity, inducing apoptosis and inhibiting neurosphere formation.
- The combination therapy led to enhanced blockage of the Shh pathway, evidenced by attenuated Gli1 expression.
Conclusions:
- The combination of TMZ and MCyp presents a promising therapeutic strategy for GBM, with an optimal ratio of 1:20.
- TMZ effectively targets tumor parenchyma, while MCyp acts as a cancer stem cell inhibitor to prevent recurrence.
- This dual-action approach offers a novel strategy for comprehensive GBM treatment, addressing both tumor growth and recurrence.
