Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers

Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers

Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-grow...

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Published in:Cancers Vol. 16; no. 1; p. 89
Main Authors: Reiners, Jr, John J, Mathieu, Patricia A, Gargano, Mary, George, Irene, Shen, Yimin, Callaghan, John F, Borch, Richard F, Mattingly, Raymond R
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 23-12-2023
MDPI
Subjects:
Analysis
Antibodies
Antitumor agents
Cancer
Care and treatment
Cell culture
Cell proliferation
Dendrimers
Farnesyltransferase
Growth
Hepatocytes
Immunoglobulins
Laboratories
Lovastatin
Neurofibromatosis
Peripheral nerves
Phosphates
Physiology
Prodrugs
Proteins
Recklinghausen's disease
Schwann cells
Sciatic nerve
Solubility
Statins
Tumors
Xenografts
Michigan
United States > US
Detroit Michigan
RAS prenylation
farnesyltransferase inhibitor
MPNST
sciatic nerve
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Summary:Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties of farnesyl monophosphate prodrug farnesyltransferase inhibitors (FTIs) on human NF1 malignant peripheral nerve sheath tumor (MPNST) cells are potentiated by co-treatment with lovastatin. Unfortunately, such prodrug FTIs have poor aqueous solubility. In this study, we synthesized a series of prodrug FTI polyamidoamine generation 4 (PAMAM G4) dendrimers that compete with farnesyl pyrophosphate for farnesyltransferase (Ftase) and assessed their effects on human NF1 MPNST S462TY cells. The prodrug 3-tert-butylfarnesyl monophosphate FTI-dendrimer (i.e., ) exhibited improved aqueous solubility. Concentrations of and lovastatin (as low as 0.1 μM) having little to no effect when used singularly synergistically suppressed cell proliferation, colony formation, and induced N-RAS, RAP1A, and RAB5A deprenylation when used in combination. Combinational treatment had no additive or synergistic effects on the proliferation/viability of immortalized normal rat Schwann cells, primary rat hepatocytes, or normal human mammary epithelial MCF10A cells. Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations.
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ISSN:2072-6694
2072-6694
DOI:10.3390/cancers16010089