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<p>Ramucirumab, a monoclonal antibody that targets vascular endothelial growth factor receptor-2 (VEGFR-2), is primarily known for its ability to inhibit angiogenesis in a variety of cancer types. Its direct cytotoxic mechanisms in colorectal cancer cells, especially those related to mitochondrial dysfunction and reactive oxygen species (ROS)-mediated apoptosis, are inadequately elucidated. This work aims to examine the involvement of mitochondrial dysfunction, oxidative stress, and caspase activation in mediating ramucirumab induced cytotoxicity in Caco-2 cells. MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide)&#xa0;and lactate dehydrogenase (LDH) tests were used to measure cell viability and cytotoxicity, respectively by exposing Caco-2 cells to ramucirumab for 24&#xa0;h. Flow cytometry was used to analyze apoptosis and cell cycle distribution. Hoechst 33342, rhodamine 123 and carboxy-H<sub>2</sub>DCFDA staining was used to examine nuclear condensation, mitochondrial membrane potential (ΔΨm) and intracellular ROS, respectively. Additionally, the expression of the apoptotic markers caspase-3 and caspase-7, and levels of VEGF was quantified. Ramucirumab enhanced the release of LDH, and significantly (<i>p</i> &lt; 0.05) decreased cell viability with increasing concentration and IC<sub>50</sub> value was estimated as 780&#xa0;µg/ ml. A significant (<i>p</i> &lt; 0.05) increase in the apoptotic cell population and cell cycle arrest primarily at the S-phase was observed. Nuclear condensation and fragmentation were observed and mitochondrial membrane potential was found to be decreased, indicating mitochondrial dysfunction. Additionally, oxidative stress (ROS) and VEGF was elevated and cleaved caspase-3 and caspase-7 were significantly upregulated, indicating caspase-mediated apoptosis. In conclusion, by causing cell cycle arrest and inducing apoptosis via mitochondrial malfunction and caspase pathway activation, ramucirumab demonstrates anti-cancer action against Caco-2 cells. These findings provide new perspectives on ramucirumab's wider anti-tumor potential beyond angiogenesis inhibition.</p>

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Ramucirumab induces apoptosis in Caco-2 cells via mitochondrial impairment and caspase activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Amal M. Al-Dogmi,
  • Khalid Mashay Al-Anazi,
  • Wajhul Qamar,
  • Mohammad Abul Farah

摘要

Ramucirumab, a monoclonal antibody that targets vascular endothelial growth factor receptor-2 (VEGFR-2), is primarily known for its ability to inhibit angiogenesis in a variety of cancer types. Its direct cytotoxic mechanisms in colorectal cancer cells, especially those related to mitochondrial dysfunction and reactive oxygen species (ROS)-mediated apoptosis, are inadequately elucidated. This work aims to examine the involvement of mitochondrial dysfunction, oxidative stress, and caspase activation in mediating ramucirumab induced cytotoxicity in Caco-2 cells. MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH) tests were used to measure cell viability and cytotoxicity, respectively by exposing Caco-2 cells to ramucirumab for 24 h. Flow cytometry was used to analyze apoptosis and cell cycle distribution. Hoechst 33342, rhodamine 123 and carboxy-H2DCFDA staining was used to examine nuclear condensation, mitochondrial membrane potential (ΔΨm) and intracellular ROS, respectively. Additionally, the expression of the apoptotic markers caspase-3 and caspase-7, and levels of VEGF was quantified. Ramucirumab enhanced the release of LDH, and significantly (p < 0.05) decreased cell viability with increasing concentration and IC50 value was estimated as 780 µg/ ml. A significant (p < 0.05) increase in the apoptotic cell population and cell cycle arrest primarily at the S-phase was observed. Nuclear condensation and fragmentation were observed and mitochondrial membrane potential was found to be decreased, indicating mitochondrial dysfunction. Additionally, oxidative stress (ROS) and VEGF was elevated and cleaved caspase-3 and caspase-7 were significantly upregulated, indicating caspase-mediated apoptosis. In conclusion, by causing cell cycle arrest and inducing apoptosis via mitochondrial malfunction and caspase pathway activation, ramucirumab demonstrates anti-cancer action against Caco-2 cells. These findings provide new perspectives on ramucirumab's wider anti-tumor potential beyond angiogenesis inhibition.