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Published on: March 28, 2021
ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair
Wenhui Jiao1,2, Shan Zhu1,2, Jingrong Shao1,2
1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Abstract:
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is used as the standard chemotherapeutic agent for GBM but with limited success, and treatment failure is mainly due to tumor resistance. One of the leading causes of TMZ resistance is the upregulation of the DNA repair mechanism. Therefore, targeting the DNA damage response (DDR) is proposed to be an effective strategy to sensitize tumor cells to TMZ. In the present study, we demonstrated that the combined use of the PI3K inhibitor ZSTK474 and TMZ showed synergetic anticancer effects on human GBM cells in vitro and in vivo. The combination treatment led to significantly increased cell apoptosis and DNA double strand breaks (DSBs). In addition, a mechanistic study indicated that TMZ enhanced the homologous recombination (HR) repair efficiency in GBM cells, while ZSTK474 impaired HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51, thereby sensitizing GBM cells to TMZ. Moreover, TMZ activated the PI3K signaling pathway through upregulation of the PI3K catalytic subunits p110α and p110β and the phosphorylation of Akt. Meanwhile, ZSTK474 blocked the activity of the PI3K/Akt pathway. Taken together, our findings suggested that the combination of ZSTK474 and TMZ might be a potential therapeutic option for GBM.
Insights
Combining PI3K inhibitor ZSTK474 with temozolomide (TMZ) shows synergistic effects against glioblastoma (GBM). This combination enhances DNA damage and apoptosis, overcoming TMZ resistance by inhibiting DNA repair pathways crucial for GBM survival.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma (GBM) is a prevalent and aggressive brain tumor with limited treatment efficacy.
- Temozolomide (TMZ) resistance, often due to DNA repair mechanisms, hinders successful GBM treatment.
- Targeting the DNA damage response (DDR) presents a promising strategy to overcome TMZ resistance.
Purpose of the Study:
- To evaluate the synergistic anticancer effects of combining PI3K inhibitor ZSTK474 with TMZ in human GBM cells.
- To elucidate the underlying mechanisms by which ZSTK474 sensitizes GBM cells to TMZ.
Main Methods:
- In vitro and in vivo studies using human GBM cells.
- Assessment of cell apoptosis and DNA double-strand breaks (DSBs).
- Mechanistic investigation of homologous recombination (HR) repair, PI3K/Akt signaling pathway, and key protein expressions (ATM, BRCA1/2, Rad51, p110α/β, Akt).
Main Results:
- Combined ZSTK474 and TMZ demonstrated synergistic anticancer effects, increasing apoptosis and DSBs in GBM cells.
- ZSTK474 impaired HR repair by inhibiting ATM phosphorylation and downregulating BRCA1/2 and Rad51 expression, sensitizing cells to TMZ.
- TMZ activated the PI3K/Akt pathway, while ZSTK474 effectively blocked this pathway.
Conclusions:
- The combination of ZSTK474 and TMZ exhibits significant synergistic anticancer activity against GBM.
- ZSTK474 overcomes TMZ resistance by disrupting DNA repair and inhibiting the PI3K/Akt pathway.
- This combination represents a potential therapeutic strategy for treating glioblastoma.
