Abstract
Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118-MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm3 and continued until tumors reached approximately 1.5-2.0 cm3. Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 749-758 |
| Number of pages | 10 |
| Journal | Journal of Molecular Medicine |
| Volume | 91 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2013 |
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Keywords
- Bevacizumab
- Dichloroacetate
- Glycolysis
- Hypoxia
- Oxidative phosphorylation
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
- Genetics(clinical)
Cite this
Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts. / Kumar, Krishan; Wigfield, Simon; Gee, Harriet E.; Devlin, Cecilia M.; Singleton, Dean; Li, Ji Liang; Buffa, Francesca; Huffman, Melanie; Sinn, Anthony L.; Silver, Jayne; Turley, Helen; Leek, Russell; Harris, Adrian L.; Ivan, Mircea.
In: Journal of Molecular Medicine, Vol. 91, No. 6, 01.06.2013, p. 749-758.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts
AU - Kumar, Krishan
AU - Wigfield, Simon
AU - Gee, Harriet E.
AU - Devlin, Cecilia M.
AU - Singleton, Dean
AU - Li, Ji Liang
AU - Buffa, Francesca
AU - Huffman, Melanie
AU - Sinn, Anthony L.
AU - Silver, Jayne
AU - Turley, Helen
AU - Leek, Russell
AU - Harris, Adrian L.
AU - Ivan, Mircea
PY - 2013/6/1
Y1 - 2013/6/1
N2 - Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118-MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm3 and continued until tumors reached approximately 1.5-2.0 cm3. Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy.
AB - Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118-MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm3 and continued until tumors reached approximately 1.5-2.0 cm3. Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy.
KW - Bevacizumab
KW - Dichloroacetate
KW - Glycolysis
KW - Hypoxia
KW - Oxidative phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=84878620894&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878620894&partnerID=8YFLogxK
U2 - 10.1007/s00109-013-0996-2
DO - 10.1007/s00109-013-0996-2
M3 - Article
C2 - 23361368
AN - SCOPUS:84878620894
VL - 91
SP - 749
EP - 758
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 6
ER -