Caffeic Acid Phenethyl Ester as a DHODH Inhibitor and Its Synergistic Anticancer Properties in Combination with 5-Fluorouracil in a Breast Cancer Cell Line

Eri Amalia,1– 3 Ajeng Diantini,1 Erwahyuni Endang Prabandari,4 Danang Waluyo,4 Anas Subarnas1 1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia; 2Department of Pharmacology, Faculty of Science and Technology, Department of Pharmacy, Muhammadiyah University, Bandung, Indonesia; 3Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia; 4Research Center for Vaccine and Drug, National Research and Innovation Agency, Bogor, IndonesiaCorrespondence: Eri Amalia, Department of Pharmaceutics and Pharmaceutical Technology, Laboratory Building 1, Faculty of Pharmacy, Universitas Padjadjaran. Jl. Raya Bandung-Sumedang km.21. Jatinangor, West Java, 45363, Indonesia, Email amalia_eri@yahoo.co.id; amalia@unpad.ac.idIntroduction: A combination of chemotherapy agents is the best choice in breast cancer treatment to increase the patient survival rate. 5-fluorouracil (5-FU) is one of the drugs applied in combination with other drugs to control and delay development of cancer cells. Nevertheless, the occurrence of multidrug resistance and dose-limiting cytotoxicity have limited the efficacy of 5-FU treatment. Therefore, the discovery of new anti-breast cancer drugs should be pursued.Objective: To study potency of a promising naturally derived compound, caffeic acid phenethyl ester (CAPE), for breast cancer treatment in single and combination with 5-FU.Methods: Cytotoxicity of CAPE, 5-FU, and 5-FU+CAPE was studied by in vitro MTT experiment in MCF-7 cell line, and RT-PCR analysis was used to evaluate the change in gene expression due to the treatment. Moreover, an enzymatic assay and molecular docking analysis were applied to evaluate the possible mechanism of substance-induced apoptosis.Results: The study revealed that a single treatment of CAPE showed cytotoxicity with IC50 6.6 ± 1.0 μM and 6.5 ± 2.9 μM at 24 h and 48 h, respectively. Meanwhile, 5-FU showed cytostatic activity. The 5-FU ...