L-Methionine accentuates anti-tumor action of Gefitinib in Gefitinib-resistant lung adenocarcinoma: Role of EGFR/ERK/AKT signaling and histone H3K36me2 alteration

In this study, we investigated the potential of L-Methionine in enhancing the cytotoxicity of Gefitinib and preventing resistance development. In vitro experiment employing the H1975 cell line demonstrated a notable enhancement in cytotoxic efficacy when L-Methionine (10 mM) was combined with Gefitinib, as indicated by a substantial reduction in IC50 values (155.854 ± 1.87 μM vs 45.83 ± 4.83 μM). Complementary in vivo investigations in a lung cancer model corroborated these findings. Co-administration of L-Methionine (100 mg/kg and 400 mg/kg) with Gefitinib (15 mg/kg) for 21 days exhibited marked improvements in therapeutic efficacy, which was observed by macroscopic and histopathological assessments. Mechanistic insights revealed that the enhanced cytotoxicity of the combination stemmed from the inhibition of the EGFR, modulating the downstream cascade of ERK/AKT and AMPK pathways. Concurrently inhibition of p-AMPK-αby the combination also disrupted metabolic homeostasis, leading to the increased production of reactive oxygen species (ROS). Notably, L-Methionine, functioning as a methyl group donor, elevated the expression of H3K36me2 (an activation mark), while reducing the p-ERK activity. Our study provides the first evidence supporting L-Methionine supplementation as a novel strategy to enhance Gefitinib chemosensitivity against pulmonary adenocarcinoma.PMID:38521369 | DOI:10.1016/j.taap.2024.116907
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Source Type: research