Broad targeting of triptolide to resistance and sensitization for cancer therapy

Article ID	Journal	Published Year	Pages	File Type
8524720	Biomedicine & Pharmacotherapy	2018	10 Pages	PDF

Abstract

Cancer cell resistance to current anticancer therapeutics as well as the side effects are still obstacles to successful cancer therapy. Hence, the development of novel anticancer agents or therapeutics is of vital significance, and especially rational adjuvant therapies containing low-cost natural products with multiple targets have attracted great interests. Triptolide, the main biocomponent of Tripterygium wilfordii Hook F, is restricted in clinical applications mainly due to its severe systemic toxicities, although it has shown strong antitumor activities in preclinical studies. Mounting evidence suggests that triptolide at low doses as an adjuvant therapeutic agent circumvents resistance to current anticancer therapies, enhances the anticancer effectiveness, and relieves toxicities of both triptolide and anticancer therapies. Furthermore, several unique antitumor targets of triptolide make it superior to other therapeutics. The molecular mechanisms of triptolide-induced anti-resistance and sensitization effects include changes in ATP-binding cassette transporters, induction of apoptosis pathways, increase in tumor suppressors and decrease in oncogenic factors, and interactions with the RNA polymerase II complex; targeting cancer stem cells and tumor-microenvironment-mediated resistance are also involved. Besides, some synthetic derivatives and novel delivery systems of triptolide are also developed to enhance the water-solubility and reduce the toxicity, which will also be discussed.

Keywords

ECM ABC CSC NF-κB CAF SAR MDR Jnk DRI HIF-1 ALDH1 Mcl-1 Bcl-2 PP2A CML Hsp PKC IAP DISC GSK3β BNIP3 HSF1 Bcl-xL PARP Bcrp GLUT pAkt EpCAM CAIX TKI Triptolide cFLIP P-gp XIAP MKP MRP1 TWHF Tripterygium wilfordii Hook F TFIIH transcription factor IIH Bcl-2 homologous antagonist killer XPB Bcl-XS repressor element-1 silencing transcription factor X-linked IAP BH3 Interacting Domain Death Agonist c-Jun N-terminal kinase MAPK MAPK phosphatase Mdm2 P-glycoprotein v-akt murine thymoma viral oncogene homolog aldehyde dehydrogenase 1 Akt antineoplastic chromatin immunoprecipitation ReST Bax BAD BIK TAM EMT Sensitization Glucose transporter murine double minute 2 Structure-activity relationship cancer stem cell combination index dose reduction index hypoxia inducible factor-1 heat shock factor 1 Vascular endothelial growth factor Vascular Endothelial Growth Factor (VEGF)nuclear factor-kappaB cancer-associated fibroblast B-cell lymphoma chronic myelogenous leukemia TNF-related apoptosis-inducing ligand Extracellular matrix Tumor-associated macrophage Bcl-2-associated death promoter Resistance Multidrug resistance Tyrosine kinase inhibitor inhibitor of apoptosis protein epithelial cell adhesion molecule Mechanism Bcl-2-associated X protein Heat shock protein protein phosphatase 2A breast cancer resistance protein multidrug resistance protein 1 mitogen-activated protein kinase BAK poly ADP-ribose polymerase BID death-inducing signaling complex CHiP Carbonic anhydrase IX ATP-binding cassette Epithelial-mesenchymal transition Glycogen synthase kinase-3β Androgen Receptor death receptor