The amide derivative of anticopalic acid induces non-apoptotic cell death in triple-negative breast cancer cells by inhibiting FAK activation

  • Sci Rep. 2023 Aug 18;13(1):13456. doi: 10.1038/s41598-023-40669-6.
Pornsuda Chawengrum  #  1 ,  Natthaorn Luepongpatthana  #  2 ,  Sanit Thongnest  3  4 ,  Jitnapa Sirirak  5 ,  Jutatip Boonsombat  6  7 ,  Kriengsak Lirdprapamongkol  8  9 ,  Siriporn Keeratichamroen  10 ,  Patcharin Kongwaen  3 ,  Phreeranat Montatip  10 ,  Prasat Kittakoop  1  3  4 ,  Jisnuson Svasti  2  10 ,  Somsak Ruchirawat  1  3  4
Affiliations
  • 1. Chemical Biology Program, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok, Thailand.
  • 2. Applied Biological Sciences Program, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok, Thailand.
  • 3. Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok, Thailand.
  • 4. Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Permanent Secretary (OPS), Ministry of Higher Education, Science, Research and Innovation (MHESI), Bangkok, Thailand.
  • 5. Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand.
  • 6. Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok, Thailand. [email protected].
  • 7. Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Permanent Secretary (OPS), Ministry of Higher Education, Science, Research and Innovation (MHESI), Bangkok, Thailand. [email protected].
  • 8. Center of Excellence on Environmental Health and Toxicology (EHT), Office of the Permanent Secretary (OPS), Ministry of Higher Education, Science, Research and Innovation (MHESI), Bangkok, Thailand. [email protected].
  • 9. Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand. [email protected].
  • 10. Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand.
  • # Contributed equally.
PMID: 37596365 DOI: 10.1038/s41598-023-40669-6
Abstract

Anticopalic acid (ACP), a labdane type diterpenoid obtained from Kaempferia elegans rhizomes, together with 21 semi-synthetic derivatives, were evaluated for their Cancer cytotoxic activity. Most derivatives displayed higher cytotoxic activity than the parent compound ACP in a panel of nine Cancer cell lines. Among the tested compounds, the amide 4p showed the highest cytotoxic activity toward leukemia cell lines, HL-60 and MOLT-3, with IC50 values of 6.81 ± 1.99 and 3.72 ± 0.26 µM, respectively. More interestingly, the amide derivative 4l exhibited cytotoxic activity with an IC50 of 13.73 ± 0.04 µM against the MDA-MB-231 triple-negative breast Cancer cell line, which is the most aggressive type of breast Cancer. Mechanistic studies revealed that 4l induced cell death in MDA-MB-231 cells through non-apoptotic regulated cell death. In addition, western blot analysis showed that compound 4l decreased the phosphorylation of FAK protein in a concentration-dependent manner. Molecular docking simulations elucidated that compound 4l could potentially inhibit FAK activation by binding to a pocket of FAK kinase domain. The data suggested that compound 4l could be a potential FAK Inhibitor for treating triple-negative breast Cancer and worth being further investigated.

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