Wogonin derivative V8 enhances bortezomib efficacy in gastric carcinoma by disrupting lysosome-mediated drug resistance

  • World J Gastroenterol. 2026 Feb 28;32(8):113299. doi: 10.3748/wjg.v32.i8.113299.
Si-Chan Li  1 ,  Shun-Zi Shao  2 ,  Yu-Hang Zhang  1 ,  Yu Zhou  1 ,  Wen-Tao Shang  1 ,  Yuan Gao  3 ,  Qi-Bin He  2 ,  Qing-Long Guo  1 ,  Chuan-Yong Guo  4 ,  Xiao-Bo Zhang  5
Affiliations
  • 1. Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, China.
  • 2. Department of Gastroenterology, Jiangning Hospital, Nanjing Medical University, Nanjing 211199, Jiangsu Province, China.
  • 3. Pharmaceutical Animal Experimental Center, China Pharmaceutical University, Nanjing 211198, Jiangsu Province, China.
  • 4. Department of Gastroenterology, Shanghai Tenth People's Hospital, Nanjing Medical University, Shanghai 200072, China.
  • 5. Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, China. [email protected].
PMID: 41809875 DOI: 10.3748/wjg.v32.i8.113299
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: In vitro 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. In vivo 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 (ATF4, 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 (P < 0.01) without organ toxicity. PDOs showed enhanced sensitivity to V8 + BTZ vs 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.

Keywords
Bortezomib; Drug resistance; Gastric carcinoma; Lysosome; Patient-derived organoids; Transcription factor EB; Wogonin derivative V8.
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