High throughput screening of natural products for LDH inhibition as an anti‐mitotic therapeutic target (585.3)

Abstract

A pathological feature hallmark of solid tumors is an over‐functional energy metabolism which results in high level production of lactic acid from glucose. The key enzyme in the production of lactate is LDH, which is highly expressed in tumor tissue and regulates substrate utilization of pyruvate to form lactate. In this study, LDH isolated from human muscle was screened using over 905 plant derived extracts to discover natural products [0.0005‐.77mg/ml] with capability to inhibit LDH. Extracts were tested using an enzyme micro‐array format and extracts containing inhibitory properties were then ranked according to their IC50's The data clearly showed that the most potent plant based LDH inhibitor was Rhus chinenesis. Through bioactivity guided chemical separations and identifications as well as kinetic and docking studies, we showed that pentagallolyl glucose, PGG, is the entity responsible for the non‐competitive inhibition of LDH‐A. We further examined several cancer cell lines viability and lactic acid production in the presence of PGG and found a decrease in viability consistent with the decrease in lactic acid production. However further studies will be required to assess if and what role inhibiting the LDH enzyme can provide in terms of adaptability and survival mechanisms involved with energy metabolism of tumor cells. Grant Funding Source: Supported by NIH grants from NIMHD G12 MD007582 and P20 MD006738

Constituents of Polygala flavescens ssp. flavescens and Their Activity as Inhibitors of Human Lactate Dehydrogenase

“…flavescens were defatted with n-hexane and extracted with methanol to afford a MeOH extract, which was partitioned between AcOEt, n-BuOH, and H 2 O to give a n-BuOH residue. This extract was subjected to size exclusion and RP-HPLC separations to afford ten new (1-10) and four known compounds (11)(12)(13)(14).…”

“…ABSTRACT: Four new flavonol glycosides (1)(2)(3)(4), two oligosaccharides (5)(6), one α-ionone (7), and three triterpenoid saponins (8)(9)(10), together with four known secondary metabolites (11)(12)(13)(14), were isolated from the aerial parts of Polygala flavescens ssp. flavescens.…”

“…So far, several LDH inhibitors have been reported in the literature, 10 and, in particular, some of them are derived from natural sources. 11,12 Therefore, the search for natural hLDH5 inhibitors represents an attractive goal to find new effective anticancer drugs and prompted the present investigation. A chemical study of P. f lavescens ssp.…”

Effect of 1,3-Oxazepine Derivative on Alkaline Phosphatase and Lactate Dehydrogenase Activity in Healthy Iraqi Females Serum

“…The changes of normal LDH activity were studied in pervious researches by using different concentrations and substances or oxygen stress (16,17). More recently, natural extracts of commonly used herbs had ability to inhibit LDH subtype A (18) Previous studies showed that the synthesized oxazepine derivatives had high antibacterial activity against E.coli, S.aureus, Salamonella typhii and moderate activity against Klebsiella pneumonia (19). Others showed highest and low bilological activity against S.aureus and no activity against E.coli(20).…”