ABSTRACT
The overexpression of the ATP-binding cassette (ABC) transporter ABCG2 has been linked to clinical multidrug resistance in solid tumors and blood cancers, which remains a significant obstacle to successful cancer chemotherapy. For years, the potential modulatory effect of bioactive compounds derived from natural sources on ABCG2-mediated multidrug resistance has been investigated, as they are inherently well tolerated and offer a broad range of chemical scaffolds. Licochalcone A (LCA), a natural chalcone isolated from the root of Glycyrrhiza inflata, is known to possess a broad spectrum of biological and pharmacological activities, including pro-apoptotic and antiproliferative effects in various cancer cell lines. In this study, the chemosensitization effect of LCA was examined in ABCG2-overexpressing multidrug-resistant cancer cells. Experimental data demonstrated that LCA inhibits the drug transport function of ABCG2 and reverses ABCG2-mediated multidrug resistance in human multidrug-resistant cancer cell lines in a concentration-dependent manner. Results of LCA-stimulated ABCG2 ATPase activity and the in silico docking analysis of LCA to the inward-open conformation of human ABCG2 suggest that LCA binds ABCG2 in the transmembrane substrate-binding pocket. This study provides evidence that LCA should be further evaluated as a modulator of ABCG2 in drug combination therapy trials against ABCG2-expressing drug-resistant tumors.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Drug Resistance, Neoplasm/drug effects , Neoplasm Proteins/antagonists & inhibitors , Adenosine Triphosphatases/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Computer Simulation , Drug Synergism , Glycyrrhiza/chemistry , Humans , Molecular Docking Simulation , Topotecan/pharmacologyABSTRACT
One of the major challenges in cancer chemotherapy is the development of multidrug resistance phenomenon attributed to the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells. Therefore, re-sensitizing MDR cancer cells to chemotherapy by directly inhibiting the activity of ABC transporters has clinical relevance. Unfortunately, previous attempts of developing clinically applicable synthetic inhibitors have failed, mostly due to problems associated with toxicity and unforeseen drug-drug interactions. An alternative approach is by repositioning drugs with known pharmacological properties as modulators of ABCB1 and ABCG2. In this study, we discovered that the transport function of ABCB1 and ABCG2 is strongly inhibited by SIS3, a specific inhibitor of Smad3. More importantly, SIS3 enhances drug-induced apoptosis and resensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic drugs at non-toxic concentrations. These findings are further supported by ATPase assays and by a docking analysis of SIS3 in the drug-binding pockets of ABCB1 and ABCG2. In summary, we revealed an additional action of SIS3 that re-sensitizes MDR cancer cells and a combination therapy with this drug and other chemotherapeutic agents may be beneficial for patients with MDR tumors.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Isoquinolines/pharmacology , Neoplasm Proteins/antagonists & inhibitors , Pyridines/pharmacology , Pyrroles/pharmacology , Smad3 Protein/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Drug Resistance, Multiple/drug effects , HEK293 Cells , Humans , MCF-7 Cells , Neoplasm Proteins/metabolismABSTRACT
INTRODUCTION: The miniscrew has been developed and effectively used as orthodontic anchorage, but current studies of its usage are insufficient to provide information about the underlying mechanical mechanisms. The aim of this study was to investigate the roles of bone quality, loading conditions, screw effects, and implanted depth on the biomechanics of an orthodontic miniscrew system by using finite element analysis. METHODS: A 3-dimensional model with a bone block integrated with a miniscrew was constructed to simulate various cortex thicknesses, cancellous bone densities, force magnitudes and directions, screw diameters and lengths, and implanted depths of miniscrews. RESULTS: Both stress and displacement increased with decreasing cortex thickness, whereas cancellous bone density played a minor role in the mechanical response. These 2 indexes were linearly proportional to the force magnitude and produced the highest values when the force was perpendicular to the long axis of the miniscrew. A wider screw provided superior mechanical advantages. The exposed length of the miniscrew was the real factor affecting mechanical performance. CONCLUSIONS: The screw diameter was the dominant factor for minscrew mechanical responses. Both bone stress and screw displacement decreased with increasing screw diameter and cortex thickness, and decreasing exposed length of the screw, force magnitude, and oblique loading direction.
