Preliminary Study On The Intervention Of HDAC Inhibitors On Intracellular Metabolomics Of Hela Cells

Metabolomics has been widely used in disease diagnosis,drug toxicity evaluation,clinical drug guidance,and drug action mechanism interpretation.Metabolic reprogramming is the survival rule of cancer cells,and histone deacetylase inhibitor(HDACI)is important in the development of anticancer drugs at present,so explore the intervention of broad-spectrum HDACIs and selective HDACIs on cancer cell metabolism.It has certain theoretical significance.First,in order to explore the similarities and differences between HDACI and other different anticancer active compounds in cancer cells,we analyzed the LC-HRMS data of different metabolite-active compounds in the laboratory before and after intervention in lung cancer A549 cells.1 There are 84 major metabolites among different anti-cancer active compounds;2 metabolite changes after Affitinib,Gefitinib and Camptothecin are similar,while Bezarotin,Cisplatin and SAHA intervene.The effect is similar,in which the laboratory anticancer activity compound LP01 has the most similar effect on A549 as SAHA;3 SAHA and LP01 both will produce phenylalanine,tyrosine and tryptophan biosynthesis in A549 cells."The three metabolic pathways have an intervention effect."Secondly,we further explored the intervention of 15 HDACIs such as CI994 on Hela cells.The experiment found that different subtypes of HDACIs have an intervention effect on the"tyrosine metabolism" pathway of cervical cancer Hela cells,Ascorbic Acid(vitamin C)and Seven metabolic pathways,such as Aldol metabolism,may also have an effect;15 HDACIs may interfere with 51 metabolites in the Tyrosine metabolic pathway,of which 6 of them are differential metabolites,such as,Benzazole-5,6-benzoquinone,L-tyrosine,L-cysteine,Fumaric acid,Ascorbic acid,Oxyglutaric acid.We analysis the changes of these 51 metabolites by hierarchical clustering thermodynamic analysis,finding that selectivity Similar HDACIs can be clustered together.Finally,we investigated the intervention of two potential HDACIs(LP01 and Q12)in the laboratory on the metabolism of Hela cells.This experiment found that:1 The effects of compounds LP01 and Q12 on the metabolic pathway of Hela cells mainly occur in Tyrosine metabolism.2,Q12 and HDAC broad-spectrum inhibitors SAHA have highest number of metabolites matches in intervention of Tyrosine metabolism(24);3 significant differential metabolites in Tyrosine metabolism affected by LP01 and HDAC I.The selective inhibitor CAY-10683 has the highest number of matches(28);4 The hierarchical cluster thermodynamic analysis of 51 differential metabolites of tyrosine metabolism also suggests that LP01 may be an HDAC class I related inhibitor,and Q12 may be a broad spectrum.HDAC inhibitor.The selective inhibition of HDAC by LP01 and Q12 will be assessed in subsequent laboratories using the kinase activity assay.