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<p>Gastric cancer (GC) is characterized by epigenetic dysregulation, metabolic plasticity, and chemoresistance, limiting the efficacy of current therapies. Targeting convergent survival pathways may therefore enhance therapeutic vulnerability. Decitabine (5-Aza-2′-deoxycytidine, 5-AZA-CdR), a DNA methyltransferase inhibitor, and metformin, an AMPK activator, modulate epigenetic and metabolic signaling, respectively, but show limited activity as monotherapies in solid tumors. Here, we investigated their combined anticancer effects in MKN45 human gastric adenocarcinoma cells. Cell viability was assessed using MTT assays, and drug interactions were quantified by fixed-ratio Chou–Talalay analysis. Apoptosis and cell-cycle progression were examined by Annexin V/propidium iodide flow cytometry, while expression of apoptosis- and autophagy-related genes (<i>CASP-1</i>,<i> CASP-3</i>,<i> BAX</i>,<i> BCL2</i>,<i> ATG7</i>) was analyzed by qRT-PCR. Functional network and pathway enrichment analyses were performed using STRING and KEGG. Metformin and decitabine reduced MKN45 cell viability in a dose- and time-dependent manner, with IC₅₀ values of 13.58 mM and 3.20 µM, respectively. Fixed-ratio combination treatment significantly enhanced antiproliferative activity, reducing the effective IC₅₀ and demonstrating strong synergism at low to moderate effect levels (Fa = 0.3–0.75; CI = 0.35–0.77), along with substantial dose-reduction effects, particularly for metformin (DRI ≈ 9.7 at Fa = 0.5). At IC₅₀-equivalent doses, combined treatment markedly increased total (32.56% ± 4.6; <i>p</i> = 0.017) and late apoptosis (19.83% ± 3.77; <i>p</i> = 0.017), induced G2/M cell-cycle arrest accompanied by depletion of G1 and S phases, indicating checkpoint activation rather than sub-G1–detectable DNA fragmentation. Mechanistically, the combination robustly upregulated CASP-1 and CASP-3, increased BAX, suppressed BCL2, elevated the BAX/BCL2 ratio, and selectively induced ATG7 expression. Network and pathway enrichment analyses highlighted apoptosis, TRAIL signaling, p53 signaling, autophagy, and platinum drug resistance pathways as key affected processes. These findings identify metabolic–epigenetic crosstalk as a therapeutic vulnerability in GC and support further preclinical evaluation of decitabine–metformin combination strategies.</p>

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Synergistic induction of apoptosis by the epigenetic modulator decitabine and metformin in gastric cancer cells highlights the potential for combination therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Mohammed AlAli,
  • Saeid Latifi-Navid,
  • Mohammad Reza Khakzad

摘要

Gastric cancer (GC) is characterized by epigenetic dysregulation, metabolic plasticity, and chemoresistance, limiting the efficacy of current therapies. Targeting convergent survival pathways may therefore enhance therapeutic vulnerability. Decitabine (5-Aza-2′-deoxycytidine, 5-AZA-CdR), a DNA methyltransferase inhibitor, and metformin, an AMPK activator, modulate epigenetic and metabolic signaling, respectively, but show limited activity as monotherapies in solid tumors. Here, we investigated their combined anticancer effects in MKN45 human gastric adenocarcinoma cells. Cell viability was assessed using MTT assays, and drug interactions were quantified by fixed-ratio Chou–Talalay analysis. Apoptosis and cell-cycle progression were examined by Annexin V/propidium iodide flow cytometry, while expression of apoptosis- and autophagy-related genes (CASP-1, CASP-3, BAX, BCL2, ATG7) was analyzed by qRT-PCR. Functional network and pathway enrichment analyses were performed using STRING and KEGG. Metformin and decitabine reduced MKN45 cell viability in a dose- and time-dependent manner, with IC₅₀ values of 13.58 mM and 3.20 µM, respectively. Fixed-ratio combination treatment significantly enhanced antiproliferative activity, reducing the effective IC₅₀ and demonstrating strong synergism at low to moderate effect levels (Fa = 0.3–0.75; CI = 0.35–0.77), along with substantial dose-reduction effects, particularly for metformin (DRI ≈ 9.7 at Fa = 0.5). At IC₅₀-equivalent doses, combined treatment markedly increased total (32.56% ± 4.6; p = 0.017) and late apoptosis (19.83% ± 3.77; p = 0.017), induced G2/M cell-cycle arrest accompanied by depletion of G1 and S phases, indicating checkpoint activation rather than sub-G1–detectable DNA fragmentation. Mechanistically, the combination robustly upregulated CASP-1 and CASP-3, increased BAX, suppressed BCL2, elevated the BAX/BCL2 ratio, and selectively induced ATG7 expression. Network and pathway enrichment analyses highlighted apoptosis, TRAIL signaling, p53 signaling, autophagy, and platinum drug resistance pathways as key affected processes. These findings identify metabolic–epigenetic crosstalk as a therapeutic vulnerability in GC and support further preclinical evaluation of decitabine–metformin combination strategies.