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

PLoS One. 2013;8(2):e56631. doi: 10.1371/journal.pone.0056631. Epub 2013 Feb 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / pathology*
  • Catechin / analogs & derivatives
  • Catechin / 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
  • Isoenzymes / genetics
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / genetics
  • Lactate Dehydrogenase 5
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis / drug effects
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • 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

Grants and funding

The work was supported by the Hong Kong Innovation and Technology Support Programme ITF funding (ITS/073/11FP), National Natural Science Foundation of China (81170647) and Projects of International Cooperation program, Guangdong Province 2012B050300014. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.