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Lopinavir inhibits meningioma cell proliferation by Akt independent mechanism

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Recent studies suggest that HIV-1 protease inhibitors may have anti-neoplastic effects on some malignancies. The anti-neoplastic effects of lopinavir have not been established or studied in brain tumors. Primary cultures of three fetal leptomeninges and 18 meningiomas were treated with lopinavir alone or with PDGF-BB. DNA synthesis was assessed by CyQUANT. Lopinavir effects on basal and PDGF-stimulated phosphorylation of the Akt-mTOR, MEK1/2-MAPK and STAT3 pathways, phosphorylation of Rb, Caspase 3 activation and reductions in survivin were assessed by Western blots. Lopinavir produced a significant reduction in PDGF-BB stimulation of DNA synthesis in a leptomeningeal culture (P = 0.0013) and 1 of 6 WHO grade I and 1 of 4 grade II meningiomas at 24 h and in 3 of 6 WHO grade I, 4 of 4 grade II and 1 of 1 grade III cell cultures (P = 0.0001) at 72 h. Lopinavir reduced PDGF-BB stimulation of phosphorylation/activation of MAPK in the 22 week fetal leptomeningeal cell cultures and in cells from 1 grade I meningioma at 24 h, but in none of 4 grade I and 5 grade II meningiomas at 6 h. Lopinavir had no notable effect on basal or PDGF-stimulated p-mTOR, p-MEK1/2, or p-STAT3, activation of Caspase 3 or survivin levels. Lopinavir treatment for 24 h had no effect on basal Rb phosphorylation but reduced Rb phosphorylation in all four meningioma cultures. These studies suggest that lopinavir may inhibit meningioma growth, and does so in part by cell cycle arrest. Additional evaluation of lopinavir as a potential adjunct chemotherapy is warranted.

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Abbreviations

p-Akt:

Phospho-Akt

HPI:

HIV-1 protease inhibitor

p-p42/44MAPK:

Phospho-p42/44 mitogen activated protein kinase

p-MEK-1/2:

Phospho-mitogen erk kinase 1/2

p-mTOR:

Phospho-mammalian target of rapamycin

PARP:

Poly (ADP ribose) polymerase 1

PDGF-BB:

Platelet derived growth factor-BB

p-STAT3:

Phospho-signal transducer and activator of transcription

p-Rb:

Phospho-retinoblastoma protein

WHO:

World Health Organization

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Acknowledgment

This work was supported by a grant from Abbott laboratories.

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Authors and Affiliations

  1. Division of Neuropathology, Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Mahlon D. Johnson & Mary O’Connell

  2. Department of Neurosurgery, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Webster Pilcher

  3. Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave., 626, Rochester, NY, 14642, USA

    Mahlon D. Johnson

Authors
  1. Mahlon D. Johnson
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  2. Mary O’Connell
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  3. Webster Pilcher
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Correspondence to Mahlon D. Johnson.

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Johnson, M.D., O’Connell, M. & Pilcher, W. Lopinavir inhibits meningioma cell proliferation by Akt independent mechanism. J Neurooncol 101, 441–448 (2011). https://doi.org/10.1007/s11060-010-0281-y

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  • DOI: https://doi.org/10.1007/s11060-010-0281-y

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