Bioactivity-guided identification and cell signaling technology to delineate the lactate dehydrogenase A inhibition effects of Spatholobus suberectus on breast cancer.

Abstract

Aerobic glycolysis is an important feature of cancer cells. In recent years, lactate dehydrogenase A (LDH-A) is emerging as a novel therapeutic target for cancer treatment. Seeking LDH-A inhibitors from natural resources has been paid much attention for drug discovery. Spatholobus suberectus (SS) is a common herbal medicine used in China for treating blood-stasis related diseases such as cancer. This study aims to explore the potential medicinal application of SS for LDH-A inhibition on breast cancer and to determine its bioactive compounds. We found that SS manifested apoptosis-inducing, cell cycle arresting and anti-LDH-A activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cell. Oral herbal extracts (1 g/kg/d) administration attenuated tumor growth and LDH-A expression in both breast cancer xenografts. Bioactivity-guided fractionation finally identified epigallocatechin as a key compound in SS inhibiting LDH-A activity. Further studies revealed that LDH-A plays a critical role in mediating the apoptosis-induction effects of epigallocatechin. The inhibited LDH-A activities by epigallocatechin is attributed to disassociation of Hsp90 from HIF-1α and subsequent accelerated HIF-1α proteasome degradation. In vivo study also demonstrated that epigallocatechin could significantly inhibit breast cancer growth, HIF-1α/LDH-A expression and trigger apoptosis without bringing toxic effects. The preclinical study thus suggests that the potential medicinal application of SS for inhibiting cancer LDH-A activity and the possibility to consider epigallocatechin as a lead compound to develop LDH-A inhibitors. Future studies of SS for chemoprevention or chemosensitization against breast cancer are thus warranted.

• Authors: Zhiyu Wang, Dongmei Wang, Shouwei Han, Neng Wang, Feizhi Mo, Tjing Yung Loo, Jiangang Shen, Hui Huang, Jianping Chen
• Journal: PloS one (PLoS One) Vol. 8 Issue 2 Pg. e56631 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23457597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• HIF1A protein, human
• HSP90 Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoenzymes
• Plant Extracts
• Reactive Oxygen Species
• Catechin
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• Proteasome Endopeptidase Complex
• gallocatechol

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (pathology)
• Catechin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Fabaceae (chemistry)
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Isoenzymes (antagonists & inhibitors, genetics)
• L-Lactate Dehydrogenase (antagonists & inhibitors, genetics)
• Lactate Dehydrogenase 5
• M Phase Cell Cycle Checkpoints (drug effects)
• Mice
• Plant Extracts (chemistry, pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis (drug effects)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays