ABSTRACT
Aberrant methylation of the transcription factor AP-2 epsilon (TFAP2E) has been attributed to 5-fluorouridine (5-FU) sensitivity. 5-Aza-2'-deoxycytidine (DAC), an epigenetic drug that inhibits DNA methylation, is able to cause reactive expression of TFAP2E by demethylating activity. This property might be useful in enhancing the sensitivity of cancer cells to 5-FU. However, the effect of DAC is transient because of its instability. Here, we report the use of intelligent gelatinases-stimuli nanoparticles (NPs) to coencapsulate and deliver DAC and 5-FU to gastric cancer (GC) cells. The results showed that NPs encapsulating DAC, 5-FU, or both could be effectively internalized by GC cells. Furthermore, we found that the NPs enhanced the stability of DAC, resulting in improved re-expression of TFAP2E. Thus, the incorporation of DAC into NPs significantly enhanced the sensitivity of GC cells to 5-FU by inhibiting cell growth rate and inducing cell apoptosis. In conclusion, the results of this study clearly demonstrated that the gelatinases-stimuli NPs are an efficient means to simultaneously deliver epigenetic and chemotherapeutic drugs that may effectively inhibit cancer cell proliferation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Nanoparticles , Stomach Neoplasms/enzymology , Apoptosis/drug effects , Azacitidine/analogs & derivatives , Azacitidine/chemistry , Azacitidine/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry, Pharmaceutical , DNA Methylation/drug effects , Decitabine , Dose-Response Relationship, Drug , Drug Stability , Enzyme Activation , Epigenesis, Genetic/drug effects , Fluorouracil/chemistry , Fluorouracil/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Time Factors , Transcription Factor AP-2/genetics , Transcription Factor AP-2/metabolismABSTRACT
Radiotherapy is the main locoregional control modality for many types of unresectable tumors, including gastric cancer. However, many patients fail radiotherapy due to intrinsic radioresistance of cancer cells, which has been found to be strongly associated with cancer stem cell (CSC)-like properties. In this study, we developed a nanoparticle formulation to deliver miR-200c, which is reported to inhibit CSC-like properties, and then evaluated its potential activity as a radiosensitizer. miR-200c nanoparticles significantly augmented radiosensitivity in three gastric cancer cell lines (sensitization enhancement ratio 1.13-1.25), but only slightly in GES-1 cells (1.06). In addition to radioenhancement, miR-200c nanoparticles reduced the expression of CD44, a putative CSC marker, and the percentage of CD44(+) BGC823 cells. Meanwhile, other CSC-like properties, including invasiveness and resistance to apoptosis, could be suppressed by miR-200c nanoparticles. CSC-associated radioresistance mechanisms, involving reactive oxygen species levels and DNA repair capacity, were also attenuated. We have demonstrated that miR-200c nanoparticles are an effective radiosensitizer in gastric cancer cells and induce little radiosensitization in normal cells, which suggests that they are as a promising candidate for further preclinical and clinical evaluation.
Subject(s)
Gelatinases/metabolism , Nanocapsules/chemistry , Peptides/pharmacokinetics , Polyesters/chemistry , Polyethylene Glycols/chemistry , Radiation-Sensitizing Agents/administration & dosage , Stomach Neoplasms/metabolism , Stomach Neoplasms/radiotherapy , Cell Line, Tumor , Escherichia coli Proteins , Humans , Nanocapsules/administration & dosage , Nanocapsules/ultrastructure , Nanocomposites/administration & dosage , Nanocomposites/chemistry , Nanocomposites/statistics & numerical data , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/radiation effects , Peptides/administration & dosage , Stomach Neoplasms/geneticsABSTRACT
Docetaxel (DOC) is widely used as radiosensitizer in various tumors, including gastric cancer (GC), but its therapeutic effect remains to be improved. In this study, using docetaxel-loaded nanoparticles (DOC-NPs) based on gelatinase-stimuli strategy, we compared their radioenhancement efficacy with docetaxel in GC. Compared with DOC, radiosensitization of DOC-NPs was improved significantly (sensitization enhancement ratio increased 1.09-fold to 1.24-fold, P<0.01) in all three gelatinase overexpressing GC cells, while increased slightly (1.02-fold, P=0.38) in gelatinase deficient normal gastric mucosa cells. The improved radiosensitization efficacy was associated with enhanced G2/M arrest, increased reactive oxygen species (ROS), more effective DSBs and promoted apoptosis. More importantly, the radiosensitization efficacy of DOC-NPs (estimated as ''very active'') was more prominent than DOC (estimated as ''moderately active'') by intravenous injection in xenograft. In conclusion, DOC-NPs are highly selective radiosensitizers in gelatinase over-expressing tumors, and more effective than DOC. By manipulating the common microenvironment difference between tumor and normal tissue, gelatinase-mediated nanoscale delivery system serves as a potential strategy possessing both universality and selectivity for radiosensitizers.
