Propolis Potentiates Methotrexate Anticancer Mechanism and Reduces its Toxic Effects

Abstract

Egyptian propolis is a powerful antioxidant and free radical scavenger produced by bees. The current study was designed to characterize Egyptian propolis, investigate its anticancer effect in vitro and its protective role against methotrexate (MTX) toxicity in Ehrlich ascites carcinoma (EAC) experimental model. Our results revealed a high content of total phenolics, flavonoids and dihydroflavonols in propolis ethanolic extract (PEE). PEE prompted cytotoxic effects in cancer cell lines and antitumor effects against EAC mice model by reducing tumor volume, count of viable tumor cells with a significant elevation in the life span as well as the mean survival time of mice. The hepatic and renal biochemical and toxicity parameters of EAC-bearing mice treated with MTX were improved by PEE. Also, it elevates the expression of Bax, caspase-3 and cytochrome-C and reduces the Bcl₂ expression in EAC cells. Moreover, PEE with MTX induced cell cycle arrest at the G0/G1 phase. Interestingly, the combination of PEE with MTX showed potent apoptosis as shown by DNA fragmentation gel, comet assay and dihydrofolate reductase level (DHFR). These findings demonstrate that Egyptian propolis extract had high chemical diversity and different antioxidant effects. Also, it optimizes the antitumor potential of MTX and declined its toxic effects.

Acknowledgment

The authors are very thankful To Prof. Dr. Mohamed A. Salem for proofreading the manuscript.

Disclosure Statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Maha M. Salem

Maha M. Salem performed acquisition of data such as Preparation of propolis extract and removal of wax, quantitative determination of total phenolics, flavonoids, flavanone and dihydroflavonols, identification and quantification of phenolic and flavonoid compounds in propolis extract, cell culture and drug treatment, biochemical assays, flow cytometry, QPCR, immunoblotting and histopathology, their data statistical analysis, drafting the article.

Thoria Donia

Thoria Donia made substantial contributions to conception and design, interpretation of data of biochemical assays and immunoblotting, revised other coauthors interpretation, revised the article, and agreed the final version of the article before submission. Submit the manuscript and respond to all reviewers comments.

Rasha Abu-Khudir

Rasha Abu-Khudir worked on acquisition of data such as quantitative determination of total phenolics, flavonoids, flavanone and dihydroflavonols, analysis and interpretation of data such as UPLC-MS spectrometry, final approval of the version to be published.

Haitham Ramadan

Haitham Ramadan performed acquisition of data such as Propolis sample collection, or analysis and interpretation of data such as UPLC-MS spectrometry, final approval of the version to be published.

Ehab M. M. Ali

Ehab M. M. Ali made substantial contributions to conception and design, revising the article critically for important intellectual content, final approval of the version to be published.

Tarek M. Mohamed

Tarek M. Mohamed made substantial contributions to conception and design, interpretation of data, revising the article critically for important intellectual content, final approval of the version to be published.