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Biological Effects of Amphiphilic Copolymer Nanoparticle-Encapsulated Multi-target Chemotherapeutic Drugs on MCF-7 Human Breast Cancer Cells

ABSTRACT: INTRODUCTION: Amphiphilic copolymer nanoparticle-encapsulated multi-target chemotherapeutic drugs have attracted considerable attention due to their favorable drug efficiency and potential application prospect. Studies have shown that an amphiphilic copolymer, methoxypoly(ethylene glycol)-poly(lactide-co-glycolide) modified with e-polylysine, and encapsulated with hydrophilic doxorubicin, hydrophobic paclitaxel and survivin siRNA profoundly improved the therapeutic effect both in vitro and in vivo.
OBJECTIVES: To investigate how MCF-7 cells would response to the exposure of these nanoparticles over with time and assess the biological effects of these nanoparticles and their encapsulated drugs in a holistic manner.
METHODS: MCF-7 cells were treated with PBS, nanocarrier and three encapsulated drugs, respectively. Metabolic alterations associated with nano-drugs exposure were investigated by performing untargeted NMR metabolomics with combination of targeted fatty acids analysis by GC-MS on cell extracts. Altered metabolic pathways were further validated by qRT-PCR approach.
RESULTS: Copolymers showed great biocompatibility with cells as it induced transit metabolic disruptions without affecting cell survival rate. The rapid release of encapsulated doxorubicin resulted in inhibition of glycolysis and DNA synthesis, active proteolysis; these metabolic alternations were recovered after 10 h exposure. However, the combination use of multiple drugs consistently induced cell cycle arrest and apoptosis evidenced by reduction in glycolysis, active proteolysis, stimulated O-GlcNAcylation, reduced the PC:GPC ratio and fatty acids accumulation. Prolonged exposure to encapsulated-multiple-drugs also induced oxidative stress to cells.
CONCLUSION: These findings provide important insight into the biological effects of nanoparticles and their encapsulated drugs while demonstrate that metabolomics is a powerful approach to evaluate the biological effects of nano-drugs.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR)

SUBMITTER: Yili Hu

PROVIDER: MTBLS430 | MetaboLights | 2018-05-03

REPOSITORIES: MetaboLights

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Project description:The environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, hypoxia. It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In the associated study we performed a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on four different cell lines in conditions of normoxia, hypoxia and anoxia. A panel of 19 commercially available drugs: 5-fluorouracil, acriflavine, bortezomib, cisplatin, digitoxin, digoxin, docetaxel, doxorubicin, etoposide, gemcitabine, irinotecan, melphalan, mitomycin c, rapamycin, sorafenib, thalidomide, tirapazamine, topotecan and vincristine were tested for cytotoxic activity on the cancer cell lines A2780 (ovarian), ACHN (renal), MCF-7 (breast), H69 (SCLC) and U-937 (lymphoma). Parallel aliquots of the cells were grown at different oxygen pressures and after 72 hours of drug exposure viability was measured with the fluorometric microculture cytotoxicity assay (FMCA). Sorafenib, irinotecan and docetaxel were in general more effective in an oxygenated environment, while cisplatin, mitomycin c and tirapazamine were more effective in a low oxygen environment. Surprisingly, hypoxia in H69 and MCF-7 cells mostly rendered higher drug sensitivity. In contrast ACHN appeared more sensitive to hypoxia, giving slower proliferating cells, and consequently, was more resistant to most drugs. Gene expression analysis was performed on MCF-7 cells after 90 hours in either anoxic or hypoxic conditions, and compared to cells grown in a regular cell incubator. The gene expression analysis was performed to validate that the cells were hypoxic/anoxic and showed the characteristic hypoxia response. Microarray based mRNA profiling was used to charactarize cells grown in hypoxia and anoxia. In the associated study we performed a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on four different cell lines in conditions of normoxia, hypoxia and anoxia. We fin that hypoxia/anoxia render cancer cells both more resistant and more sensistive, depending of the type of drug used. The gene expression analysis was performed to validate that the cells really were hypoxic/anoxic and showed the characteristic hypoxia response. The cell line used for the gene expression analysis was MCF-7.

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Biological Effects of Amphiphilic Copolymer Nanoparticle-Encapsulated Multi-target Chemotherapeutic Drugs on MCF-7 Human Breast Cancer Cells

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