Although clinical outcomes of some cancer have been greatly improved by advancements made in surgery, chemo or radiotherapy and development of novel strategies such as molecular targeted therapy, Traditional Chinese Medicine (TCM) is particularly appreciated for cancer therapy in China based on its 5,000-year-old history, well established theoretical system and numerous exciting case reports. However, due to lack of quality assurance, laboratory evidences and well-designed clinical trials, TCM always encounters much skepticism and pessimism by the West. The study aims to identify the bioactive compounds in a Chinese herb Spatholobus suberectus (SS, 雞血藤) by targeting on lactate dehydrogenase A (LDH-A) in breast cancer.
Glycolysis inhibition has been considered as important strategy to block cancer energy metabolism and therefore suppressing cancer growth. LDH-A has been demonstrated to be up-regulated in various cancer cells. In our study, 46 breast cancer specimens were collected to study the relation between LDH-A expression and clinicopathological characteristics including menopause, tumor size, node involvement, differentiation and pathological subtypes classified by estrogen receptor (ER), progesterone receptor (PR) and Her-2. LDH-A expression was found to be correlated significantly with breast cancer size and independent with other clinicopathological factors. LDH-A silencing in breast cancer cell lines MDA-MB-231 and MCF-7 resulted in an inhibited breast cancer cell proliferation, elevated intracellular oxidative stress, induction of mitochondiral pathway apoptosis and limited tumorigenic ability, indicating that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.
SS is historically recommended to invigorate blood circulation and has been prescribed to treat diseases relating to blood stasis syndromes including menstrual abnormalities, anemia, numbness of the limbs, arthritis and cancer, etc. Our following study revealed that SS aqueous extracts could significantly inhibited breast cancer LDH-A expression and activity in both in vitro and in vivo models built by MDA-MB-231 and MCF-7 cell lines. Bioactivity guided fractionation based on LDH-A activity, apoptosis and LDH-A expression further identified epigallocatechin (EGC) as the key compound responsible for the inhibited LDH-A expression.
Mechanistic studies found that the inhibitory effect of EGC on LDH-A expression was mainly through promoting Hypoxia inducible factor-1α (HIF-1α) proteasome degradation rather than inhibiting transcription activity, which might be correlated with decreased binding between HIF-1α and Hsp90. Consistent with in vitro findings, EGC was also demonstrated effecitve in suppressing breast cancer growth in vivo correlating to down-regulation of LDH-A, HIF-1α and triggerment of apoptosis.
This study provides preliminary laboratory evidences for applying SS in breast cancer therapy. However, further research is needed to evaluate its metabolism, the synergistic effects with chemotherapeutic agents and clinical efficiency. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/188741 |
| Date | January 2012 |
| Creators | Wang, Zhiyu, 王志宇 |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B48329423 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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