Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms

• Published in: Toxicology and applied pharmacology Vol. 316; pp. 27 - 35
• Main Authors: Gaballah, Hanaa H., Gaber, Rasha A., Mohamed, Darin A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2017
• Subjects: 5-FU; 60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; Animals; Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apigenin; Apigenin - administration & dosage; APOPTOSIS; Apoptosis - drug effects; Apoptosis - physiology; Autophay; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - metabolism; CARCINOMAS; Cell Death - drug effects; Cell Death - physiology; Drug Synergism; Ehrlich tumor; ENZYME IMMUNOASSAY; FLAVONOIDS; Fluorouracil - administration & dosage; FLUOROURACILS; FRUITS; GLUTATHIONE; IN VIVO; JNK activity; Ki-67 Antigen - biosynthesis; Male; MAP Kinase Kinase 4 - metabolism; MESSENGER-RNA; MICE; Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis; PEROXIDASES; POLYMERASE CHAIN REACTION; THERAPY; Tumor Burden - drug effects; Tumor Burden - physiology; VEGETABLES; Xenograft Model Antitumor Assays - methods; Ehrlich tumor; Apigenin; JNK activity; Autophay; 5-FU; Apoptosis
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.12.012

Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention.
This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC).
Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis.
5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group.
The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice.
•Apigenin potentiated 5-FU cytotoxicity in EAC solid tumor models in vivo.•It acted via autophagy stimulation, downregulating MCL-1 and Ki-67 expression.•It caused JNK activation and ROS accumulation; resulted in tumor growth inhibition.•Apigenin can be used as a co-adjuvant agent in cancer therapy.