Wogonin derivative V8 enhances bortezomib efficacy in gastric carcinoma by disrupting lysosome-mediated drug resistance.
[BACKGROUND] Bortezomib (BTZ) is ineffective in gastric carcinoma (GC) due to lysosome-mediated resistance.
APA
Li SC, Shao SZ, et al. (2026). Wogonin derivative V8 enhances bortezomib efficacy in gastric carcinoma by disrupting lysosome-mediated drug resistance.. World journal of gastroenterology, 32(8), 113299. https://doi.org/10.3748/wjg.v32.i8.113299
MLA
Li SC, et al.. "Wogonin derivative V8 enhances bortezomib efficacy in gastric carcinoma by disrupting lysosome-mediated drug resistance.." World journal of gastroenterology, vol. 32, no. 8, 2026, pp. 113299.
PMID
41809875
Abstract
[BACKGROUND] Bortezomib (BTZ) is ineffective in gastric carcinoma (GC) due to lysosome-mediated resistance. Wogonin derivative V8 targets lysosomes.
[AIM] To address the limited efficacy of BTZ in GC and explore whether wogonin derivative V8 enhances anti-GC effects by overcoming lysosome-mediated resistance.
[METHODS] experiments used four human GC cell lines (MGC-803, BGC-823, AGS, and HGC-27) to assess cell viability (cell counting kit-8), lysosomal function (LysoSensor staining), autophagy (western blotting for light chain 3/p62), and drug synergy [combination index (CI)]. Liquid chromatography/mass spectrometry measured intracellular BTZ concentration. Transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, was investigated using small interfering RNA silencing and plasmid overexpression. efficacy/safety was tested in MGC-803 xenograft nude mice, and patient-derived tumor organoids (PDOs) validated clinical relevance.
[RESULTS] BTZ was trapped in GC cell lysosomes, reducing its proteasome accessibility and inducing resistance; lysosome number correlated positively with the half-maximal inhibitory concentration of BTZ. V8 induced lysosomal damage/deacidification, increasing intracellular BTZ availability. V8 + BTZ synergistically inhibited GC cell growth (CI < 1), upregulated proteotoxic stress markers (, immunoglobulin heavy chain binding protein) and apoptotic mediators (cleaved caspase-3). TFEB knockdown enhanced V8 + BTZ cytotoxicity, whereas its overexpression reduced cell death, indicating a protective role of TFEB in gastric cancer cells. In xenografts, V8 + BTZ significantly reduced tumor volume/weight ( < 0.01) without organ toxicity. PDOs showed enhanced sensitivity to V8 + BTZ monotherapy.
[CONCLUSION] Lysosomes mediate BTZ resistance in GC; V8 overcomes this by disrupting lysosomes, enabling BTZ to target proteasomes. V8 + BTZ is a safe, effective strategy against GC.
[AIM] To address the limited efficacy of BTZ in GC and explore whether wogonin derivative V8 enhances anti-GC effects by overcoming lysosome-mediated resistance.
[METHODS] experiments used four human GC cell lines (MGC-803, BGC-823, AGS, and HGC-27) to assess cell viability (cell counting kit-8), lysosomal function (LysoSensor staining), autophagy (western blotting for light chain 3/p62), and drug synergy [combination index (CI)]. Liquid chromatography/mass spectrometry measured intracellular BTZ concentration. Transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, was investigated using small interfering RNA silencing and plasmid overexpression. efficacy/safety was tested in MGC-803 xenograft nude mice, and patient-derived tumor organoids (PDOs) validated clinical relevance.
[RESULTS] BTZ was trapped in GC cell lysosomes, reducing its proteasome accessibility and inducing resistance; lysosome number correlated positively with the half-maximal inhibitory concentration of BTZ. V8 induced lysosomal damage/deacidification, increasing intracellular BTZ availability. V8 + BTZ synergistically inhibited GC cell growth (CI < 1), upregulated proteotoxic stress markers (, immunoglobulin heavy chain binding protein) and apoptotic mediators (cleaved caspase-3). TFEB knockdown enhanced V8 + BTZ cytotoxicity, whereas its overexpression reduced cell death, indicating a protective role of TFEB in gastric cancer cells. In xenografts, V8 + BTZ significantly reduced tumor volume/weight ( < 0.01) without organ toxicity. PDOs showed enhanced sensitivity to V8 + BTZ monotherapy.
[CONCLUSION] Lysosomes mediate BTZ resistance in GC; V8 overcomes this by disrupting lysosomes, enabling BTZ to target proteasomes. V8 + BTZ is a safe, effective strategy against GC.
MeSH Terms
Humans; Stomach Neoplasms; Animals; Drug Resistance, Neoplasm; Lysosomes; Bortezomib; Cell Line, Tumor; Xenograft Model Antitumor Assays; Mice; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Flavanones; Mice, Nude; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Cell Survival; Apoptosis
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