Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma

by Selleckchem | Aug 15 2023

Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wnt/β-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT. Pharmacological inhibition of the serine synthesis pathway with a highly selective inhibitor NCT503 synergistically works with temozolomide in inhibiting O6-methylguanine DNA methyltransferase (MGMT)-positive glioblastoma cell growth and inducing apoptosis both in vitro and in vivo. Mechanistically, NCT503 treatment reduces MGMT expression possibly via Wnt/βcatenin pathway. Reactive oxygen species-mediated DNA damage is at least partially involved. Combinational administration of NCT503 and TMZ may represent a novel and promising treatment strategy to enhance TMZ efficacy in patients with MGMT-high glioblastoma.

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The provided text describes a study that investigated the potential of a compound called NCT503 to enhance the efficacy of temozolomide (TMZ) chemotherapy in glioblastoma (GBM), specifically in GBMs with high expression of O6-methylguanine DNA methyltransferase (MGMT). GBM is a highly malignant brain tumor, and TMZ is the standard chemotherapeutic agent used in its treatment. However, chemoresistance is a significant challenge in GBM therapy.

The study focused on the de novo serine synthesis pathway (SSP), which is a metabolic pathway involved in cancer progression and chemotherapy resistance. The researchers used NCT503, a selective inhibitor of phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the SSP, to examine whether inhibiting this pathway could enhance the effectiveness of TMZ in MGMT-positive GBMs.

The researchers conducted various experiments using GBM cell lines (T98G and U118) and patient-derived GBM xenograft models. They employed assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and colony formation to assess cell growth, apoptosis, and the combined effects of NCT503 and TMZ treatment.

The results showed that NCT503 and TMZ acted synergistically to suppress GBM cell growth and induce apoptosis in vitro. In the GBM xenograft models, the combined treatment inhibited tumor growth and promoted apoptosis more effectively than either treatment alone. The study also investigated the mechanism behind these findings. It suggested that NCT503 treatment reduced MGMT expression, possibly by modulating the Wnt/β-catenin pathway. Furthermore, the combined treatment led to increased levels of reactive oxygen species (ROS) within the cells, and the synergistic effects could be partially reversed by using NAC, a scavenger of ROS.

In summary, the study demonstrated that NCT503, an inhibitor of the serine synthesis pathway, when used in combination with TMZ, showed promise in inhibiting GBM cell growth and inducing apoptosis, particularly in MGMT-positive GBMs. The findings suggested that NCT503 may enhance the efficacy of TMZ in GBM treatment, and the combination of NCT503 and TMZ could be a potential novel therapeutic strategy for MGMT-high glioblastoma patients.