Research progress of drug resistance mechanism of temozolomide in the treatment of glioblastoma

Abstract

Glioblastoma, the most malignant primary brain tumor among gliomas, is characterized by a low cure rate, high recurrence rate, and invasive growth. Without chemotherapy, the median survival of patients is only 12.1 months. The standard treatment for glioblastoma primarily involves surgical resection, complemented by radiotherapy. Temozolomide (TMZ), a new oral alkylating agent, is currently used as the first-line chemotherapy drug for glioma. However, TMZ treatment only improves median survival by 2 months, largely because of the tumor's ability to develop resistance to the drug. The main mechanism underlying this resistance involves DNA repair processes, such as the action of O6⁃methylguanine DNA methyltransferase (MGMT), which repairs the DNA damage caused by TMZ, and other DNA repair mechanisms including mismatch repair and base excision repair. These mechanisms can effectively repair the DNA damage caused by TMZ, thereby reducing the sensitivity of tumor cells to the drug. This study summarized the recent research progress of TMZ resistance mechanism in glioblastoma, aiming to provide a theoretical basis for the development of new therapies. The mechanisms of glioma resistance to TMZ mainly involves DNA damage repair (as mentioned above), abnormal cell signaling pathways (p53-mediated signaling, reactive oxygen species-mediated signaling, endoplasmic reticulum stress and autophagy-related signaling, receptor tyrosine kinase-related signaling, transforming growth factors, β-mediated signaling pathway, Wnt/β-Catenin signaling pathway), glioma stem cells, tumor microenvironment (hypoxic microenvironment, nano-drug delivery system), epidermal growth factor receptor, and microRNAs.

Keywords

• Glioma
• Temozolomide
• DNA repair mechanism
• Signal pathway
• Resistance mechanism