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Derrischalcone suppresses cholangiocarcinoma cells through targeting ROS-mediated mitochondrial cell death, Akt/mTOR, and FAK pathways

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Abstract

Chemotherapy is a palliative treatment for unresectable patients with cholangiocarcinoma (CCA). However, drug resistance is a major cause of the failure of this treatment. Derrischalcone (DC), a novel chalcone isolated from Derris indica fruit, has been shown pharmacologically active; though, the effect of DC on CCA is unknown. The present study investigated the cytotoxic, antiproliferative, anti-migration, and anti-invasion effects and underlying mechanisms of DC on CCA KKU-M156 and KKU-100 cells. Cytotoxicity and apoptosis were evaluated by acridine orange and ethidium bromide fluorescent staining. Reactive oxygen species (ROS) was measured by dihydroethidium assay. Cell proliferation and reproductive cell death were assessed by sulforhodamine B staining and colony-forming assay. Migration and invasion were determined by wound healing and transwell chamber assays. Protein expressions associated with cell death, proliferation, migration, and invasion were analyzed by western immunoblotting. We found that DC induced cytotoxicity and apoptosis in association with ROS formation and oxidative stress. Treatment with N-acetylcysteine suppressed ROS formation and attenuated DC-induced cytotoxic and apoptotic effects. DC increased the expression of p53, p21, Bax, and cytochrome c proteins in association with cell death. DC-induced antiproliferation, colony formation, anti-migration, and anti-invasion were associated with the suppression of Akt/mTOR/cyclin D1 and FAK signaling pathways. These findings suggest that the multi-targeting strategies with DC may be a novel treatment for cancer therapy.

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Acknowledgements

The authors thank Mr. Kevin McCracken for editing the manuscript via Publication Clinic, Khon Kaen University, Khon Kaen, Thailand.

Funding

This research project was supported by the National Research Council of Thailand through Khon Kaen University, Khon Kaen, Thailand (No. 61003302), Grant-in-Aid from the Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand (IN60127), and grant support by Mahasarakham University, Mahasarakham, Thailand (Grant No. 6308016/2563).

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Authors and Affiliations

  1. Faculty of Veterinary Sciences, Mahasarakham University, Mahasarakham, 44000, Thailand

    Jaroon Wandee & Piyarat Srinontong

  2. Bioveterinary Research Unit, Faculty of Veterinary Sciences, Mahasarakham University, Mahasarakham, 44000, Thailand

    Jaroon Wandee & Piyarat Srinontong

  3. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Auemduan Prawan, Laddawan Senggunprai, Sarinya Kongpetch & Veerapol Kukongviriyapan

  4. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand

    Auemduan Prawan, Laddawan Senggunprai, Sarinya Kongpetch & Veerapol Kukongviriyapan

  5. Natural Products Research Unit, Department of Chemistry, Faculty of Science, Center of Excellence for Innovation in Chemistry, Khon Kaen University, Khon Kaen, 40002, Thailand

    Chavi Yenjai

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  1. Jaroon Wandee
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  2. Piyarat Srinontong
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  3. Auemduan Prawan
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  4. Laddawan Senggunprai
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  7. Veerapol Kukongviriyapan
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Contributions

JW and VK conceived the study. JW, SK, LS, AP, and VK designed the study. CY collected and prepared study material. JW and PS performed the experiments. JW and VK wrote the manuscript. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

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Correspondence to Jaroon Wandee or Veerapol Kukongviriyapan.

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Wandee, J., Srinontong, P., Prawan, A. et al. Derrischalcone suppresses cholangiocarcinoma cells through targeting ROS-mediated mitochondrial cell death, Akt/mTOR, and FAK pathways. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1929–1940 (2021). https://doi.org/10.1007/s00210-021-02102-5

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