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Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.(ORIGINAL RESEARCH)(Report)

Background: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposo... Full description

Journal Title: International Journal of Nanomedicine 2015, Vol.10, p.4405(19)
Main Author: Gandham, Srujan Kumar
Other Authors: Talekar, Meghna , Singh, Amit , Amiji, Mansoor M.
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 1178-2013 ; DOI: 10.2147/IJN.S82818
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recordid: gale_ofa446735165
title: Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.(ORIGINAL RESEARCH)(Report)
format: Article
creator:
  • Gandham, Srujan Kumar
  • Talekar, Meghna
  • Singh, Amit
  • Amiji, Mansoor M.
subjects:
  • Ovarian Cancer – Research
  • Ovarian Cancer – Care and Treatment
  • Ovarian Cancer – Complications and Side Effects
  • Epidermal Growth Factors – Research
  • Epidermal Growth Factors – Influence
  • Glucose Metabolism – Analysis
  • Glycolysis – Analysis
ispartof: International Journal of Nanomedicine, 2015, Vol.10, p.4405(19)
description: Background: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Methods: Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. Results: SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 [micro]m by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (PC0.0001, Student's t-test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect (PC0.001, Student's t-test, unpaired and two-tailed) at a dose of 50 [micro]M than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 [micro]M-100 [micro]M) showed that the liposomal formulations had an enhanced cytotoxic effect of 2-5-fold (PC0.0001, Student's t-test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 [micro]M and 25 [micro]M concentrations. Conclusion: SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer cells. Encapsulation of 3-BPA in a liposomal formulation improved permeability, HK2 inhibition, and cytotoxicity in the multicellular spheroid model. Keywords: ovarian cancer, aerobic glycolysis, hexokinase-2, 3-bromopyruvate, epidermal growth factor receptor-targeted liposomes
language: eng
source:
identifier: ISSN: 1178-2013 ; DOI: 10.2147/IJN.S82818
fulltext: fulltext
issn:
  • 1178-2013
  • 11782013
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titleInhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.(ORIGINAL RESEARCH)(Report)
creatorGandham, Srujan Kumar ; Talekar, Meghna ; Singh, Amit ; Amiji, Mansoor M.
ispartofInternational Journal of Nanomedicine, 2015, Vol.10, p.4405(19)
identifierISSN: 1178-2013 ; DOI: 10.2147/IJN.S82818
subjectOvarian Cancer – Research ; Ovarian Cancer – Care and Treatment ; Ovarian Cancer – Complications and Side Effects ; Epidermal Growth Factors – Research ; Epidermal Growth Factors – Influence ; Glucose Metabolism – Analysis ; Glycolysis – Analysis
descriptionBackground: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Methods: Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. Results: SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 [micro]m by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (PC0.0001, Student's t-test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect (PC0.001, Student's t-test, unpaired and two-tailed) at a dose of 50 [micro]M than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 [micro]M-100 [micro]M) showed that the liposomal formulations had an enhanced cytotoxic effect of 2-5-fold (PC0.0001, Student's t-test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 [micro]M and 25 [micro]M concentrations. Conclusion: SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer cells. Encapsulation of 3-BPA in a liposomal formulation improved permeability, HK2 inhibition, and cytotoxicity in the multicellular spheroid model. Keywords: ovarian cancer, aerobic glycolysis, hexokinase-2, 3-bromopyruvate, epidermal growth factor receptor-targeted liposomes
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titleInhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.(ORIGINAL RESEARCH)(Report)
descriptionBackground: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Methods: Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. Results: SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 [micro]m by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (PC0.0001, Student's t-test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect (PC0.001, Student's t-test, unpaired and two-tailed) at a dose of 50 [micro]M than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 [micro]M-100 [micro]M) showed that the liposomal formulations had an enhanced cytotoxic effect of 2-5-fold (PC0.0001, Student's t-test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 [micro]M and 25 [micro]M concentrations. Conclusion: SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer cells. Encapsulation of 3-BPA in a liposomal formulation improved permeability, HK2 inhibition, and cytotoxicity in the multicellular spheroid model. Keywords: ovarian cancer, aerobic glycolysis, hexokinase-2, 3-bromopyruvate, epidermal growth factor receptor-targeted liposomes
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3Epidermal growth factors–Research
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titleInhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.(ORIGINAL RESEARCH)(Report)
authorGandham, Srujan Kumar ; Talekar, Meghna ; Singh, Amit ; Amiji, Mansoor M.
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abstractBackground: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Methods: Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. Results: SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 [micro]m by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (PC0.0001, Student's t-test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect (PC0.001, Student's t-test, unpaired and two-tailed) at a dose of 50 [micro]M than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 [micro]M-100 [micro]M) showed that the liposomal formulations had an enhanced cytotoxic effect of 2-5-fold (PC0.0001, Student's t-test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 [micro]M and 25 [micro]M concentrations. Conclusion: SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer cells. Encapsulation of 3-BPA in a liposomal formulation improved permeability, HK2 inhibition, and cytotoxicity in the multicellular spheroid model. Keywords: ovarian cancer, aerobic glycolysis, hexokinase-2, 3-bromopyruvate, epidermal growth factor receptor-targeted liposomes
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