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Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.

Schlaepfer IR, Glodé LM, Hitz CA, Pac CT, Boyle KE, Maroni P, Deep G, Agarwal R, Lucia SM, Cramer SD, Serkova NJ, Eckel RH - Mol Imaging Biol (2015)

Bottom Line: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines.Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro.PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, MS 8117 12801 E. 17th Ave, Room L18-8101D, Aurora, CO, 80045, USA, isabel.schlaepfer@ucdenver.edu.

ABSTRACT

Purpose: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose.

Procedures: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h.

Results: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

Conclusions: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.

No MeSH data available.


Related in: MedlinePlus

[18F]FDG uptake is enhanced in VCaP xenografts after systemic treatment with etomoxir. a) Representative axial (left) and coronal images of a subcutaneous xenograft mouse model before (basal, top) and after etomoxir injection (bottom). Right tumor is indicated with white arrow. Note the increased uptake of [18F]FDG in the heart with etomoxir treatment. This systemic effect was observed in all the mouse models. The scale bar represents signal activity as a function of radioactivity. b) Normalized uptake values (NUV) fold change for xenografts examined by FDG-PET, *P = 0.035 t test between etomoxir and water-treated tumors. c) Representative western blot of VCaP tumor lysates from mice treated with vehicle (water 1, 2) or etomoxir 20 mg/kg (3–8) systemically for 24 h. d) Radioactive counts from [14C]palmitate oxidation in VCaP tumor homogenates incubated ex vivo with water or etomoxir (150 μM) for 45 min.
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Fig4: [18F]FDG uptake is enhanced in VCaP xenografts after systemic treatment with etomoxir. a) Representative axial (left) and coronal images of a subcutaneous xenograft mouse model before (basal, top) and after etomoxir injection (bottom). Right tumor is indicated with white arrow. Note the increased uptake of [18F]FDG in the heart with etomoxir treatment. This systemic effect was observed in all the mouse models. The scale bar represents signal activity as a function of radioactivity. b) Normalized uptake values (NUV) fold change for xenografts examined by FDG-PET, *P = 0.035 t test between etomoxir and water-treated tumors. c) Representative western blot of VCaP tumor lysates from mice treated with vehicle (water 1, 2) or etomoxir 20 mg/kg (3–8) systemically for 24 h. d) Radioactive counts from [14C]palmitate oxidation in VCaP tumor homogenates incubated ex vivo with water or etomoxir (150 μM) for 45 min.

Mentions: To investigate if this flare of enhanced glucose uptake effect could also be happening in vivo, we used three mouse models of PCa: subcutaneous xenografts with VCaP cells (n = 16), orthotopic xenografts with PC3-Luciferase cells (n = 4), and genetic TRAMP mouse models (n = 6). All mice were treated with 20 mg/kg of etomoxir by IP injection after a basal PET scan and subjected to another PET scan after 24 h. Fig. 4a shows representative images of the before (basal) and after scans of the subcutaneous xenografts, showing increased glucose uptake (white > orange). Green color reflects the lowest uptake. Notice that the tumor (white arrow) is barely visible in the basal scan but becomes visible in 24 h with treatment. Fig. 4b shows the significant fold change difference (P = 0.03) in normalized glucose uptake values (NUV) between the etomoxir and water-treated subcutaneous tumors. Student’s paired t test of the before and after measurements for each etomoxir-treated mouse also showed a significant fold change in uptake (1.4 ± 0.3, P = 0.001). When we examined the NUV fold change in the mouse prostate tissue, the [18F]FDG uptake was minimal in the healthy prostate gland, close to the background activity. Etomoxir did not produce significant changes over basal scan (0.96 ± 0.07). Mice treated with vehicle (water) showed the same result, (1.0 ± 0.04). However, as expected, significant NUV fold changes were observed in leg muscle (1.32 ± 1.2, P < 0.01), subscapular brown adipose tissue or BAT (1.43 ± 1.3, P < 0.001) and heart (2.52 ± 0.75, P = 0.02) compared with basal scans. Additionally, to make the study more relevant for clinical imaging purposes, tumor-to-tissue total activity ratios were also calculated. As shown in Table 2, we observed a significant tumor/prostate ratio increase after systemic etomoxir (P ≤ 0.03). The tumor/muscle ratios with etomoxir were also significantly increased, reflecting the systemic effect of etomoxir in muscle tissue.Fig. 4


Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.

Schlaepfer IR, Glodé LM, Hitz CA, Pac CT, Boyle KE, Maroni P, Deep G, Agarwal R, Lucia SM, Cramer SD, Serkova NJ, Eckel RH - Mol Imaging Biol (2015)

[18F]FDG uptake is enhanced in VCaP xenografts after systemic treatment with etomoxir. a) Representative axial (left) and coronal images of a subcutaneous xenograft mouse model before (basal, top) and after etomoxir injection (bottom). Right tumor is indicated with white arrow. Note the increased uptake of [18F]FDG in the heart with etomoxir treatment. This systemic effect was observed in all the mouse models. The scale bar represents signal activity as a function of radioactivity. b) Normalized uptake values (NUV) fold change for xenografts examined by FDG-PET, *P = 0.035 t test between etomoxir and water-treated tumors. c) Representative western blot of VCaP tumor lysates from mice treated with vehicle (water 1, 2) or etomoxir 20 mg/kg (3–8) systemically for 24 h. d) Radioactive counts from [14C]palmitate oxidation in VCaP tumor homogenates incubated ex vivo with water or etomoxir (150 μM) for 45 min.
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Related In: Results  -  Collection

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Fig4: [18F]FDG uptake is enhanced in VCaP xenografts after systemic treatment with etomoxir. a) Representative axial (left) and coronal images of a subcutaneous xenograft mouse model before (basal, top) and after etomoxir injection (bottom). Right tumor is indicated with white arrow. Note the increased uptake of [18F]FDG in the heart with etomoxir treatment. This systemic effect was observed in all the mouse models. The scale bar represents signal activity as a function of radioactivity. b) Normalized uptake values (NUV) fold change for xenografts examined by FDG-PET, *P = 0.035 t test between etomoxir and water-treated tumors. c) Representative western blot of VCaP tumor lysates from mice treated with vehicle (water 1, 2) or etomoxir 20 mg/kg (3–8) systemically for 24 h. d) Radioactive counts from [14C]palmitate oxidation in VCaP tumor homogenates incubated ex vivo with water or etomoxir (150 μM) for 45 min.
Mentions: To investigate if this flare of enhanced glucose uptake effect could also be happening in vivo, we used three mouse models of PCa: subcutaneous xenografts with VCaP cells (n = 16), orthotopic xenografts with PC3-Luciferase cells (n = 4), and genetic TRAMP mouse models (n = 6). All mice were treated with 20 mg/kg of etomoxir by IP injection after a basal PET scan and subjected to another PET scan after 24 h. Fig. 4a shows representative images of the before (basal) and after scans of the subcutaneous xenografts, showing increased glucose uptake (white > orange). Green color reflects the lowest uptake. Notice that the tumor (white arrow) is barely visible in the basal scan but becomes visible in 24 h with treatment. Fig. 4b shows the significant fold change difference (P = 0.03) in normalized glucose uptake values (NUV) between the etomoxir and water-treated subcutaneous tumors. Student’s paired t test of the before and after measurements for each etomoxir-treated mouse also showed a significant fold change in uptake (1.4 ± 0.3, P = 0.001). When we examined the NUV fold change in the mouse prostate tissue, the [18F]FDG uptake was minimal in the healthy prostate gland, close to the background activity. Etomoxir did not produce significant changes over basal scan (0.96 ± 0.07). Mice treated with vehicle (water) showed the same result, (1.0 ± 0.04). However, as expected, significant NUV fold changes were observed in leg muscle (1.32 ± 1.2, P < 0.01), subscapular brown adipose tissue or BAT (1.43 ± 1.3, P < 0.001) and heart (2.52 ± 0.75, P = 0.02) compared with basal scans. Additionally, to make the study more relevant for clinical imaging purposes, tumor-to-tissue total activity ratios were also calculated. As shown in Table 2, we observed a significant tumor/prostate ratio increase after systemic etomoxir (P ≤ 0.03). The tumor/muscle ratios with etomoxir were also significantly increased, reflecting the systemic effect of etomoxir in muscle tissue.Fig. 4

Bottom Line: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines.Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro.PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, MS 8117 12801 E. 17th Ave, Room L18-8101D, Aurora, CO, 80045, USA, isabel.schlaepfer@ucdenver.edu.

ABSTRACT

Purpose: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose.

Procedures: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h.

Results: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.

Conclusions: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.

No MeSH data available.


Related in: MedlinePlus