FM19G11 inhibits O⁶‐methylguanine DNA‐methyltransferase expression under both hypoxic and normoxic conditions

Abstract

FM19G11 is a small molecular agent that inhibits hypoxia‐inducible factor‐1‐alpha (HIF‐1α) and other signaling pathways. In this study, we characterized the modulating effects of FM19G11 on O6‐methylguanine DNA‐methyltransferase (MGMT), the main regulator of temozolomide (TMZ) resistance in glioblastomas. This study included 2 MGMT‐positive cell lines (GBM‐XD and T98G). MGMT promoter methylation status, mRNA abundance, and protein levels were determined before and after FM19G11 treatment, and the roles of various signaling pathways were characterized. Under hypoxic conditions, MGMT mRNA and protein levels were significantly downregulated by FM19G11 via the HIF‐1α pathway in both GBM‐XD and T98G cells. In normoxic culture, T98G cells were strongly positive for MGMT, and MGMT expression was substantially downregulated by FM19G11 via the NF‐κB pathway. In addition, TMZ resistance was reversed by treatment with FM19G11. Meanwhile, FM19G11 has no cytotoxicity at its effective dose. FM19G11 could potentially be used to counteract TMZ resistance in MGMT‐positive glioblastomas.

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

“…Postoperative adjuvant chemotherapy plays an important role in Stupp's regimen, and TMZ is the first choice for chemotherapeutic agents. The addition of TMZ can bring additional benefits to patients with gliomas for an additional average 2.5 months to overall survival (OS) . However, the emergence of TMZ resistance in the majority of GBM patients brings another great challenge to the treatment of patients …”

“…The alkylating agent TMZ can spontaneously dissolve into the reactive intermediate 5‐(3‐methyl‐1‐triazeno)imidazole‐4‐carboxamide in the human body, and then it methylates the N 7 /O 6 positions of guanine and the N 3 position of adenine . The most important mismatch in these 3 methylation positions is the O 6 position of guanine (O 6 ‐G), which causes DNA base mispairing by continuously inducing O 6 ‐methylguanine adduct, finally leading to cell cycle arrest and cellular apoptosis.…”

“…Western blot assay was carried out as previously described . Cells were washed with PBS and then lysed with RIPA lysis buffer (Solarbio, China) and protease inhibitors (Roche Applied Science, Indianapolis, Switzerland).…”

Quenching Epigenetic Drug Resistance Using Antihypoxic Microparticles in Glioblastoma Patient‐Derived Chips

“…[ 4c,20 ] A significant part of this process is the action of hypoxia, which can alter the epigenetic program of tumor cells. [ 8a,21 ] This spontaneous process promotes cancer cell survival by repairing antiapoptosis genes, thus interfering with the DNA damaging action of anticancer drugs. Therefore, drug resistance increases in growing tumors with the activation of aggressive cell invasiveness toward metastasis.…”