Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance has been identified as a major cause of failure of cancer treatment. Due to their relative non-toxicity, selenium nanoparticles (SeNPs) have been reported as excellent cancer therapeutic nanodrugs. In this study, we designed and prepared a novel nanosystem with borneol surface-functionalized and liver targeting to overcome the multidrug resistance. Borneol (Bor)-modified SeNPs can significantly improve the stability of SeNPs and their anticancer activity. Fe(PiP)3 (PiP = 2-phenylimidazo [4,5-f][1,10] phenanthroline) is a novel anticancer agent with low solubility and stability. In this study, we have constructed a functionalized SeNPs (GAL/Bor@SeNPs) by the surface decoration of galactosamine (GAL), which is a liver targeting ligand that significantly enhanced the cellular uptake of Fe(PiP)3-loaded nanosystem via dynamin-mediated lipid raft endocytosis and clathrin-mediated endocytosis in liver cancer cells overexpressing asialoglycoprotein receptor, thus achieving amplified anticancer efficacy. This multifunctional nanosystem exhibited excellent hemocompatibility and anticancer activity comparing with Fe(PiP)3 or SeNPs alone. Remarkably, GAL/Bor@SeNPs antagonized the multidrug resistance in R-HepG2 cells by inhibiting the expression of ABC family proteins, resulting in enhanced drug accumulation and retention. Internalized nanoparticles released free iron complexes into the cytoplasm, which triggered ROS down-regulation and induced apoptosis through activating AKT and MAPKs pathways. Moreover, this nanosystem effectively prolonged the circulation time of encapsulated drugs. Taken together, this study suggests that GAL and Bor functionalization could be an effective strategy to design cancer-targeted nanomaterials to antagonize multidrug resistance in cancers.
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PMID:Construction of a cancer-targeted nanosystem as a payload of iron complexes to reverse cancer multidrug resistance. 3226 77

Background: Lung cancer has a high mortality rate and is resistant to multiple chemotherapeutics. Natural Borneol (NB) is a monoterpenoid compound that facilitates the bioavailability of drugs. In this study, we investigated the effects of NB on chemosensitivity in the A549 human lung adenocarcinoma cell line and to elucidate therapeutic molecular target of NB. Methods: The chemosensitivity effects of NB in A549 cells were examined by MTT assay. The mechanism of NB action was evaluated using flow cytometry and Western blotting assays. Surface plasmon resonance (SPR) and LC-MS combined analysis (MS-SPRi) was performed to elucidate the candidate molecular target of NB. The chemosensitizing capacity of NB in vivo was assessed in nude mice bearing A549 tumors. Results: NB pretreatment sensitized A549 cells to low doxorubicin (DOX) dosage, leading to a 15.7% to 41.5% increase in apoptosis. This increase was correlated with ERK and AKT inactivation and activation of phospho-p38 MAPK, phospho-JNK, and phosphor-p53. Furthermore, this synergism depends on reactive oxygen species (ROS) generation. MS-SPRi analysis revealed that transient receptor potential melastatin-8 (TRPM8) is the candidate target of NB in potentiating DOX killing potency. Genetically, TRPM8 knock-down significantly suppresses the chemosensitizing effects of NB and inhibits ROS generation through restraining calcium mobilization. Moreover, pretreatment with NB synergistically enhances the anticancer effects of DOX to delay tumor progression in vivo. Conclusions: These results suggest that TRPM8 may be a valid therapeutic target in the potential application of NB, and show that NB is a chemosensitizer for lung cancer treatment.
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PMID:TRPM8-regulated calcium mobilization plays a critical role in synergistic chemosensitization of Borneol on Doxorubicin. 3292 40