UM E-Theses Collection (澳門大學電子學位論文庫)
Title
Discovery of two compounds from Chinese herbal medicine to reverse cancer drug resistance
English Abstract
As a major public health problem, cancer is currently the second leading cause of death, and is expected to exceed heart diseases as the leading cause of death in the next couple of years. Although chemotherapy is an important therapeutic strategy for cancer, serious adverse effects and therapeutic resistance are commonly observed in most cancers. Cancer drug resistance is a complicated phenomenon that affects patients with a variety of cancers. However, current therapies used to address cancer resistance yield limited success in clinic. Therefore, overcoming drug resistance is one of the most urgent goals in cancer research. Overexpression of ATP-binding cassette (ABC) transporters and anti-apoptotic molecules are the two most common reasons that engender cancer resistance. This study was designed to target ABC transporter P-glycoprotein (P-gp) and cancerspecific apoptosis machineries to identify potential candidates from Chinese medicine for reversing cancer drug resistance. Two small natural compounds, namely schisandrin B (Sch B) and gambogic acid (GA), are identified to reverse cancer drug resistance through different mechanisms. Our findings demonstrated that Sch B could sensitize doxorubicin (Dox)-resistant breast cancer cells to Dox-induced apoptosis. Sch B exerted the effect via the regulation of two pathways: (1) inhibiting the expression and activity of P-gp to increase the intracellular accumulation of Dox; (2) preferentially promoting chymotryptic activities of the proteasome to facilitate proteasome-mediated degradation of anti-apoptotic protein survivin. These findings indicate that simultaneously targeting P-gp and survivin may be a novel therapeutic strategy for breast cancer that are resistant against Dox-based therapies. Further studies are iv needed to define the pharmacokinetic properties of Sch B and the effects of the combined treatment with in vivo models of resistant breast cancer. Next, we evaluated the potential of GA in reversing P-gp-independent TNF-related apoptosis-inducing ligand (TRAIL) resistance. Our results showed that subtoxic concentration of TRAIL and GA synergistically induced apoptosis in TRAILresistant breast cancer cells. GA did not upregulate the expression of death receptors (DRs), but cooperated with TRAIL to activate Bid and decrease the levels of antiapoptotic proteins to promote the crosstalk of extrinsic and intrinsic apoptotic signaling. We further successfully applied hyaluronic acid (HA) coated PEI-PLGA nanoparticles (NPs) as a nanocarrier system to simultaneously deliver GA and therapeutic TRAIL plasmid (pTRAIL) to improve curative effect of triple-negative breast cancer (TNBC). The NPs loading dual-agents exhibited satisfactory basic physicochemical characteristics and showed improved therapeutic effect in both in vitro and in vivo of TNBC. This multifunctional NP system efficiently co-delivered GA and pTRAIL thus represents a promising therapy to treat TNBC by manipulating different molecular targets. Collectively, our findings indicate that Chinese medicine, with the aid of nanotechnology, may play a noteworthy role in discovering new candidates and strategies for the fight against cancer drug resistance.
Issue Date
2016
Author
Wang, Sheng Peng,
Faculty
Institute of Chinese Medical Sciences
Degree
Ph.D.
Subject
Drug resistance in cancer cells
Medicinal plants -- China
Biomedical Sciences -- Institute of Chinese Medical Sciences


Supervisor
王一濤
Library URL
b3592672
Files In This Item:
Full-text (Internet)
Location
1/F Zone C
Supervisor
--