title: 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: School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors: Zhiyu
authors: Z
authors: Wang
authors: Dongmei
authors: D
authors: Wang
authors: Shouwei
authors: S
authors: Han
authors: Neng
authors: N
authors: Wang
authors: Feizhi
authors: F
authors: Mo
authors: Tjing Yung
authors: TY
authors: Loo
authors: Jiangang
authors: J
authors: Shen
authors: Hui
authors: H
authors: Huang
authors: Jianping
authors: J
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007887:Fabaceae / Q000737:chemistry*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000080864:Lactate Dehydrogenase 5; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D002392:Catechin; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D046988:Proteasome Endopeptidase Complex; C057580:gallocatechol