Oridonin inhibits Hela cell proliferation via downregulation of glutathione metabolism: a new insight from metabolomics

Abstract

Objectives: This study aims to elucidate Oridonin' s inhibitory mechanism to cervical cancer using metabolomics methods and pharmacological assays.

Methods: Network pharmacology and KEGG pathway analysis are used to identify overlapped targets and involved metabolic pathways. UPLC-MS/MS metabolomics analysis is used to determine altered metabolites after Oridonin treatment. Other bioassays are also employed to uncover the changes in critical molecules that are highly related to altered metabolites.

Key findings: Seventy-five overlapped targets are identified between Oridonin and cervical cancer. Twenty-one metabolites involved in tricarboxylic acid cycle glutathione metabolism, branched-chain amino acid metabolism and so on changes significantly after Oridonin treatment. Oridonin treatment significantly reduces the content of cysteine and inhibit the catalytic activity of glutamine-cysteine ligase subunit, a rate-limiting enzyme for the synthesis of glutathione. As a result, the content of glutathione is also reduced. The antioxidant enzyme glutathione peroxidase 4 which uses glutathione as a cofactor, is inactivated, resulting in a burst release of reactive oxygen species. The ATP content is also significantly reduced in Hela cells after Oridonin treatment.

Conclusions: This study finds that Oridonin treatment induces Hela cell apoptosis possibly via inhibition of the glutathione metabolism.

Keywords: cell apoptosis; cervical cancer; glutathione metabolism; metabolomics; oridonin; reactive oxygen species.