The Resource Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells, Megha Barot

Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells, Megha Barot

Label
Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells
Title
Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells
Statement of responsibility
Megha Barot
Creator
Contributor
Author
Degree supervisor
Subject
Genre
Language
eng
Summary
Chemoreduction is the key treatment for retinoblastoma management. However, anticancer agents suffer from poor cell permeability and chemoresistance due to major interaction with multidrug resistant (MDR) efflux proteins (MDR1 and MRP2) over-expressed on retinoblastoma tumor. Ocular cells have shown good tolerability against antimicrobial moxifloxacin (fourth generation fluoroquinolone) at higher dose level. As majority of fluoroquinolones become ineffective due to efflux mediated acquired drug resistance therefore, we have first determined an interaction of moxifloxacin with efflux (MDR1 and MRP2) transporters. Our results provides direct evidence that moxifloxacin is an overlapping substrate of MDR1 and MRP2 efflux transporters. Since, literature has evident co-administration of overlapping drug substrate as a viable strategy to overcome MDR. Therefore, we have tested moxifloxacin potential to overcome chemoresistance in retinoblastoma. Our results showed that 2-2.5 fold increased uptakes of three anticancer drugs (etoposide, topotecan and vinblastine) were observed in the presence of moxifloxacin across model cell lines suggesting moxifloxacin mediated evasion of efflux pumps. Significant reductions in efflux ratio of these anticancer agents were also observed in the presence of moxifloxacin indicating moxifloxacin mediated improved anticancer transport. Following cytotoxicity study, tenfold reduction in IC50 value of topotecan and etoposide and twofold reduction in IC50 value of vinblastine was observed in the presence of moxifloxacin. Significant enhancement of anticancer mediated caspase-3 enzyme activity and reduction in proinflammatory cytokines (IL-8 and IL-6) release were also observed in the presence of moxifloxacin. There is a need to further explore this finding to confirm its clinical feasibility, if proven, ultimately it will aid to reduce the chemotherapeutic dose and associated dose-limiting toxicities. Considering the fact that most drug targets are indeed contained within specific intracellular compartments, the ability of a drug to accumulate into these sites is a critical determinant in the observed drug response. Mitochondrion is an attractive target for drug-delivery because there is a growing confirmation to support an association between mitochondrial dysfunctions and a number of ocular diseases. A range of possibilities exist for the selective drug delivery to the mitochondria one among such is a transporter targeted strategy. Localization of various influx and efflux transporters is generally considered to be restricted to cell surface level. However, cellular compartments may also be a potential site for these transporters. The functional localization of both efflux (MDR1) and influx (PepT-1) transporters in the mitochondrial membrane of primary corneal epithelial cells was studied. Isolation and purification of mitochondria was performed by optimized cell fractionation method. Functional activity of MDR1 and PepT-1 transporter was assessed by performing in vitro uptake studies on isolated mitochondria. Molecular characterization of both transporters was confirmed by western blot and confocal analysis. This knowledge of mitochondrial existence of MDR1 and PepT-1transporter may aid in the development of subcellular ocular drug delivery strategies
Cataloging source
UMK
http://library.link/vocab/creatorDate
1983-
http://library.link/vocab/creatorName
Barot, Megha
Degree
Ph.D.
Dissertation note
(School of Pharmacy and Department of Chemistry).
Dissertation year
2013.
Granting institution
University of Missouri-Kansas City,
Illustrations
illustrations
Index
no index present
Literary form
non fiction
Nature of contents
  • dictionaries
  • bibliography
  • theses
http://library.link/vocab/relatedWorkOrContributorDate
1954-
http://library.link/vocab/relatedWorkOrContributorName
Mitra, Ashim K.
http://library.link/vocab/subjectName
  • Retinoblastoma
  • Chemotherapy
Label
Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells, Megha Barot
Instantiates
Publication
Note
  • "A dissertation in Pharmaceutical Sciences and Chemistry."
  • Advisor: Ashim K. Mitra
  • Vita
Antecedent source
not applicable
Bibliography note
Includes bibliographical references (pages 152-167)
Carrier category
online resource
Carrier category code
  • cr
Carrier MARC source
rdacarrier.
Color
black and white
Content category
text
Content type code
  • txt
Content type MARC source
rdacontent.
Contents
Literature review -- Moxifloxacin interaction with transporters and anticancer agents for retinoblastoma management -- Interaction of moxiflaxacin with influx transporter -- Interaction of moxifloxacin with anticancer agents for retinoblastoma management -- Mitochondrial localization of transporters -- Mitochondrial localization of p-glycoprotein and peptide transporters in corneal epithelial cells - Novel strategies for intracellualr drug targeting -- Summary and recommendations
Control code
909914516
Dimensions
unknown
Extent
1 online resource (168 pages)
File format
one file format
Form of item
online
Level of compression
mixed
Media category
computer
Media MARC source
rdamedia.
Media type code
  • c
Other physical details
illustrations.
Quality assurance targets
not applicable
Specific material designation
remote
System control number
(OCoLC)909914516
System details
  • The full text of the dissertation is available as an Adobe Acrobat .pdf file; Adobe Acrobat Reader required to view the file
  • Mode of access: World Wide Web
Label
Novel drug interaction for improving intracellular accumulation and efficacy of chemotherapeutics in retinoblastoma and mitochondrial localization of transporters in corneal epithelial cells, Megha Barot
Publication
Note
  • "A dissertation in Pharmaceutical Sciences and Chemistry."
  • Advisor: Ashim K. Mitra
  • Vita
Antecedent source
not applicable
Bibliography note
Includes bibliographical references (pages 152-167)
Carrier category
online resource
Carrier category code
  • cr
Carrier MARC source
rdacarrier.
Color
black and white
Content category
text
Content type code
  • txt
Content type MARC source
rdacontent.
Contents
Literature review -- Moxifloxacin interaction with transporters and anticancer agents for retinoblastoma management -- Interaction of moxiflaxacin with influx transporter -- Interaction of moxifloxacin with anticancer agents for retinoblastoma management -- Mitochondrial localization of transporters -- Mitochondrial localization of p-glycoprotein and peptide transporters in corneal epithelial cells - Novel strategies for intracellualr drug targeting -- Summary and recommendations
Control code
909914516
Dimensions
unknown
Extent
1 online resource (168 pages)
File format
one file format
Form of item
online
Level of compression
mixed
Media category
computer
Media MARC source
rdamedia.
Media type code
  • c
Other physical details
illustrations.
Quality assurance targets
not applicable
Specific material designation
remote
System control number
(OCoLC)909914516
System details
  • The full text of the dissertation is available as an Adobe Acrobat .pdf file; Adobe Acrobat Reader required to view the file
  • Mode of access: World Wide Web

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