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.
Highlights
Cancer cells can be distinguished from normal cells in several hallmarks including sustaining proliferative signaling, avoiding immune destruction, resisting cell death, genome instability and disordering angiogenesis, etc [1]
Cell cycle analysis showed that in SS treated breast cancer cells, there has a significant increase in G2/M subpopulation, implying that the G2/M checkpoint was arrested by SS (Figure 1C)
As reactive oxygen species (ROS) has been reported as an important inductor of apoptosis and DNA damage, and O22 accumulation was observed as an important subsequent event following lactate dehydrogenase A (LDH-A) inhibition, hydroethidine was applied to detect the change of intracellular O22 level after SS administration
Summary
Cancer cells can be distinguished from normal cells in several hallmarks including sustaining proliferative signaling, avoiding immune destruction, resisting cell death, genome instability and disordering angiogenesis, etc [1]. One of the hallmarks is that cancer cells have a fundamentally different bioenergetic metabolism from that of non-neoplastic cells [2,3]. Energetic metabolism mainly relies upon the mitochondrial oxidative phosphorylation. Due to the hypoxia microenvironment and mitochondrial gene mutations, cancer cells have developed altered metabolism that predominantly produce energy by glycolysis, even in the presence of oxygen this is known as the ‘‘Warburg Effect’’ [4]. Targeting on glycolysis pathway has already become an important strategy for cancer diagnosis and treatment in clinic [5]
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