Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines

Sandeep R. Bhave, David Y.A. Dadey, Rowan M. Karvas, Daniel J. Ferraro, Rama P. Kotipatruni, Jerry J. Jaboin, Andrew N. Hallahan, Todd DeWees, Amanda G. Linkous, Dennis E. Hallahan, Dinesh Thotala

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P = 0.002 and 17.9% in U87-MG; P = 0.012), decreased invasion (35.6% in GL261; P = 0.0037 and 31.8% in U87-MG; P = 0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P = 0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3, however combination of PF-8380 (10 mg/kg) Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy.

Original languageEnglish (US)
Article numberArticle 236
JournalFrontiers in Oncology
Volume3 SEP
DOIs
StatePublished - Dec 31 2013
Externally publishedYes

Fingerprint

Radiation Tolerance
Glioblastoma
Cell Line
Neoplasms
Radiation
Survival
Radiotherapy
6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one
Tumor Burden
Radio
Immunoblotting
Brain Neoplasms
Phosphorylation
Skin

Keywords

  • Autotaxin
  • Glioblastoma
  • Lysophosphatidic acid
  • PF-8380
  • Radiosensitizer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bhave, S. R., Dadey, D. Y. A., Karvas, R. M., Ferraro, D. J., Kotipatruni, R. P., Jaboin, J. J., ... Thotala, D. (2013). Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines. Frontiers in Oncology, 3 SEP, [Article 236]. https://doi.org/10.3389/fonc.2013.00236

Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines. / Bhave, Sandeep R.; Dadey, David Y.A.; Karvas, Rowan M.; Ferraro, Daniel J.; Kotipatruni, Rama P.; Jaboin, Jerry J.; Hallahan, Andrew N.; DeWees, Todd; Linkous, Amanda G.; Hallahan, Dennis E.; Thotala, Dinesh.

In: Frontiers in Oncology, Vol. 3 SEP, Article 236, 31.12.2013.

Research output: Contribution to journalArticle

Bhave, SR, Dadey, DYA, Karvas, RM, Ferraro, DJ, Kotipatruni, RP, Jaboin, JJ, Hallahan, AN, DeWees, T, Linkous, AG, Hallahan, DE & Thotala, D 2013, 'Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines', Frontiers in Oncology, vol. 3 SEP, Article 236. https://doi.org/10.3389/fonc.2013.00236
Bhave SR, Dadey DYA, Karvas RM, Ferraro DJ, Kotipatruni RP, Jaboin JJ et al. Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines. Frontiers in Oncology. 2013 Dec 31;3 SEP. Article 236. https://doi.org/10.3389/fonc.2013.00236
Bhave, Sandeep R. ; Dadey, David Y.A. ; Karvas, Rowan M. ; Ferraro, Daniel J. ; Kotipatruni, Rama P. ; Jaboin, Jerry J. ; Hallahan, Andrew N. ; DeWees, Todd ; Linkous, Amanda G. ; Hallahan, Dennis E. ; Thotala, Dinesh. / Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines. In: Frontiers in Oncology. 2013 ; Vol. 3 SEP.
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abstract = "Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration (33{\%} in GL261; P = 0.002 and 17.9{\%} in U87-MG; P = 0.012), decreased invasion (35.6{\%} in GL261; P = 0.0037 and 31.8{\%} in U87-MG; P = 0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65{\%}; P = 0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3, however combination of PF-8380 (10 mg/kg) Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy.",
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AU - Bhave, Sandeep R.

AU - Dadey, David Y.A.

AU - Karvas, Rowan M.

AU - Ferraro, Daniel J.

AU - Kotipatruni, Rama P.

AU - Jaboin, Jerry J.

AU - Hallahan, Andrew N.

AU - DeWees, Todd

AU - Linkous, Amanda G.

AU - Hallahan, Dennis E.

AU - Thotala, Dinesh

PY - 2013/12/31

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N2 - Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P = 0.002 and 17.9% in U87-MG; P = 0.012), decreased invasion (35.6% in GL261; P = 0.0037 and 31.8% in U87-MG; P = 0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P = 0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3, however combination of PF-8380 (10 mg/kg) Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy.

AB - Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P = 0.002 and 17.9% in U87-MG; P = 0.012), decreased invasion (35.6% in GL261; P = 0.0037 and 31.8% in U87-MG; P = 0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P = 0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3, however combination of PF-8380 (10 mg/kg) Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy.

KW - Autotaxin

KW - Glioblastoma

KW - Lysophosphatidic acid

KW - PF-8380

KW - Radiosensitizer

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