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