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<p>The present study used an in-vivo inflammation-induced colorectal cancer (CRC) model to evaluate the additive effect of thapsigargin (TG) with the standard chemotherapy drug irinotecan (IRN). CRC was induced by AOM/DSS, and after 10th weeks, animals were treated with five weekly cycles of either IRN or TG or a combination of both drugs. All the animals were sacrificed after the 16th week, and the data were analysed. Coadministration of both IRN and TG substantially reduced both tumor numbers and occurrence of aberrant crypt foci (ACF) in the colon tissues as compared to only IRN/TG-treated animal groups. Further analyses revealed that IRN and TG together alleviated ultrastructural abnormalities of the colon with a recovered overall histoarchitecture, enhanced ER stress and mitochondrial dysfunction, reduction of PCNA positive cells indicating low rate of cellular proliferation, increased DNA fragmentation and apoptosis supported by higher intensity of γH2AX and cleaved caspase-3 immunohistochemistry. Gene expression analyses of key oncogenic biomarkers also suggest that the addition of TG with IRN is more effective in inhibiting carcinogenic transformation in the colon of AOM/DSS-treated mice. This study provides direct evidence of the superior therapeutic potential of a combination of both drugs compared to conventional monotherapy in the management of CRC.</p>

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Thapsigargin enhanced chemotherapeutic sensitivity of irinotecan in the inflammation-induced colorectal cancer model in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Sukanya Baruah,
  • Manuj Kumar Bharali,
  • Nabila Akhtara,
  • Jaydeep Kumar Nath,
  • Sabana Sargam Rahman,
  • Shehnaz Siddika Rasid,
  • Mitali Baidya,
  • Epham Mayum Mohd Samir Khan,
  • Ritu Mishra

摘要

The present study used an in-vivo inflammation-induced colorectal cancer (CRC) model to evaluate the additive effect of thapsigargin (TG) with the standard chemotherapy drug irinotecan (IRN). CRC was induced by AOM/DSS, and after 10th weeks, animals were treated with five weekly cycles of either IRN or TG or a combination of both drugs. All the animals were sacrificed after the 16th week, and the data were analysed. Coadministration of both IRN and TG substantially reduced both tumor numbers and occurrence of aberrant crypt foci (ACF) in the colon tissues as compared to only IRN/TG-treated animal groups. Further analyses revealed that IRN and TG together alleviated ultrastructural abnormalities of the colon with a recovered overall histoarchitecture, enhanced ER stress and mitochondrial dysfunction, reduction of PCNA positive cells indicating low rate of cellular proliferation, increased DNA fragmentation and apoptosis supported by higher intensity of γH2AX and cleaved caspase-3 immunohistochemistry. Gene expression analyses of key oncogenic biomarkers also suggest that the addition of TG with IRN is more effective in inhibiting carcinogenic transformation in the colon of AOM/DSS-treated mice. This study provides direct evidence of the superior therapeutic potential of a combination of both drugs compared to conventional monotherapy in the management of CRC.