and Evaluation of Ethanolic Crude Extracts on Fatty Acid Synthase Expression on Breast Cancer Cells

Overview

Journal Biomedicine (Taipei)

Specialty Biomedical Engineering

Date 2024 Jun 28

PMID 38939097

Authors

Nur Amanina Johari

Nur Anisa Sapii

Alvin Lu Jiunn Hieng

Nurriza Ab Latif

Syazwani Itri Amran

Rosnani Hasham

Khairunadwa Jemon

Affiliations

Soon will be listed here.

Abstract

Background: Fatty acid synthase (FASN), a key rate-limiting enzyme in the fatty acid biosynthesis pathway has been identified to be overexpressed in breast cancer. This overexpression has been affiliated with poor prognosis and resistance to chemotherapeutics. Consequently, FASN has come into focus as an appealing potential target for breast cancer treatment. Available FASN inhibitors, however, are unstable and have been correlated with adverse side effects.

Objective: This present study aims to investigate the potential of ethanolic crude extract (AP) as a potent FASN inhibitor in breast cancer cells.

Materials & Methods: This study used MTT assay and flow cytometry analysis to measure cell viability and apoptosis following AP treatment (0-500 μg/mL). Furthermore, FASN protein expression was evaluated using immunocytochemistry whereas lipid droplet formation was quantified using Oil Red O staining. Literature-based identified AP phytochemicals were subjected to the prediction of molecular docking and ADMET properties.

Results: This study demonstrated that AP significantly reduced cell viability while inducing apoptosis in breast cancer cells. In addition, for the first time, exposure to AP was demonstrated to drastically reduce intracellular FASN protein expression and lipid droplet accumulation in EMT6 and MCF-7 breast cancer cells. Docking simulation analysis demonstrated AP phytochemicals may have exerted an inhibitory effect by targeting the FASN Thioesterase (TE) domain similarly to the known FASN inhibitor, Orlistat. Moreover, all AP phytochemicals also possessed drug-likeness properties which are in accordance with Lipinski's rule of five.

Conclusions: These results highlight the potential of ethanolic crude extract as a FASN inhibitor and hence might have the potential to be further developed as a potent chemotherapeutic drug for breast cancer treatment.

References

Akbar S . Andrographis paniculata: a review of pharmacological activities and clinical effects. Altern Med Rev. 2011; 16(1):66-77. View

Do-Won Jeong , Lee S, Chun Y . How cancer cells remodel lipid metabolism: strategies targeting transcription factors. Lipids Health Dis. 2021; 20(1):163. PMC: 8590761. DOI: 10.1186/s12944-021-01593-8. View

Floris A, Mazarei M, Yang X, Robinson A, Zhou J, Barberis A . SUMOylation Protects FASN Against Proteasomal Degradation in Breast Cancer Cells Treated with Grape Leaf Extract. Biomolecules. 2020; 10(4). PMC: 7226518. DOI: 10.3390/biom10040529. View

Chao W, Lin B . Isolation and identification of bioactive compounds in Andrographis paniculata (Chuanxinlian). Chin Med. 2010; 5:17. PMC: 2881933. DOI: 10.1186/1749-8546-5-17. View

Sukardiman H, Widyawaruyanti A, Sismindari , Zaini N . Apoptosis inducing effect of andrographolide on TD-47 human breast cancer cell line. Afr J Tradit Complement Altern Med. 2010; 4(3):345-51. PMC: 2816486. DOI: 10.4314/ajtcam.v4i3.31228. View

Lin H, Lii C, Chen H, Lin A, Yang Y, Chen H . Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages. Am J Chin Med. 2018; 46(1):87-106. DOI: 10.1142/S0192415X18500052. View

Rae C, Fragkoulis G, Chalmers A . Cytotoxicity and Radiosensitizing Activity of the Fatty Acid Synthase Inhibitor C75 Is Enhanced by Blocking Fatty Acid Uptake in Prostate Cancer Cells. Adv Radiat Oncol. 2020; 5(5):994-1005. PMC: 7557210. DOI: 10.1016/j.adro.2020.06.022. View

Hsieh C, Huang Y . Aspirin Breaks the Crosstalk between 3T3-L1 Adipocytes and 4T1 Breast Cancer Cells by Regulating Cytokine Production. PLoS One. 2016; 11(1):e0147161. PMC: 4721678. DOI: 10.1371/journal.pone.0147161. View

Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P . Breast cancer. Nat Rev Dis Primers. 2019; 5(1):66. DOI: 10.1038/s41572-019-0111-2. View

10.

Fhu C, Ali A . Fatty Acid Synthase: An Emerging Target in Cancer. Molecules. 2020; 25(17). PMC: 7504791. DOI: 10.3390/molecules25173935. View

11.

Li L, Yue G, Fung K, Yu J, Lau C, Chiu P . Combined use of and chemotherapeutics for metastatic oesophageal cancer: a pre-clinical study. Hong Kong Med J. 2020; 25 Suppl 9(6):43-46. View

12.

Flavin R, Peluso S, Nguyen P, Loda M . Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010; 6(4):551-62. PMC: 3197858. DOI: 10.2217/fon.10.11. View

13.

Cheng F, Wang Q, Chen M, Quiocho F, Ma J . Molecular docking study of the interactions between the thioesterase domain of human fatty acid synthase and its ligands. Proteins. 2007; 70(4):1228-34. DOI: 10.1002/prot.21615. View

14.

Sheeja K, Guruvayoorappan C, Kuttan G . Antiangiogenic activity of Andrographis paniculata extract and andrographolide. Int Immunopharmacol. 2006; 7(2):211-21. DOI: 10.1016/j.intimp.2006.10.002. View

15.

Dos Santos D, Carlos de Souza J, Massariol Pimenta T, da Silva Martins B, Junior R, Silva Butzene S . The impact of lipid metabolism on breast cancer: a review about its role in tumorigenesis and immune escape. Cell Commun Signal. 2023; 21(1):161. PMC: 10304265. DOI: 10.1186/s12964-023-01178-1. View

16.

Zhao C, Hu W, Xu Y, Wang D, Wang Y, Lv W . Current Landscape: The Mechanism and Therapeutic Impact of Obesity for Breast Cancer. Front Oncol. 2021; 11:704893. PMC: 8326839. DOI: 10.3389/fonc.2021.704893. View

17.

Malahubban M, Alimon A, Sazili A, Fakurazi S, Zakry F . Phytochemical analysis of Andrographis paniculata and Orthosiphon stamineus leaf extracts for their antibacterial and antioxidant potential. Trop Biomed. 2013; 30(3):467-80. View

18.

Sareer O, Ahmad S, Umar S . Andrographis paniculata: a critical appraisal of extraction, isolation and quantification of andrographolide and other active constituents. Nat Prod Res. 2014; 28(23):2081-101. DOI: 10.1080/14786419.2014.924004. View

19.

Wang Y, Nie F, Ouyang J, Wang X, Ma X . Inhibitory effects of sea buckthorn procyanidins on fatty acid synthase and MDA-MB-231 cells. Tumour Biol. 2014; 35(10):9563-9. DOI: 10.1007/s13277-014-2233-1. View

20.

Peng Y, Wang Y, Tang N, Sun D, Lan Y, Yu Z . Andrographolide inhibits breast cancer through suppressing COX-2 expression and angiogenesis via inactivation of p300 signaling and VEGF pathway. J Exp Clin Cancer Res. 2018; 37(1):248. PMC: 6186120. DOI: 10.1186/s13046-018-0926-9. View