In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway

Staci L Haney; Michelle L Varney; Yashpal Chhonker; Geoffrey Talmon; Lynette M Smith; Daryl J Murry; Sarah A Holstein

doi:10.1016/j.phrs.2021.105528

In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway

Pharmacol Res. 2021 May:167:105528. doi: 10.1016/j.phrs.2021.105528. Epub 2021 Mar 3.

Authors

Staci L Haney¹, Michelle L Varney¹, Yashpal Chhonker², Geoffrey Talmon³, Lynette M Smith⁴, Daryl J Murry⁵, Sarah A Holstein⁶

Affiliations

¹ Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
² Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁴ College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁵ Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁶ Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: sarah.holstein@unmc.edu.

Abstract

Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthetic pathway (IBP), produces the isoprenoid (geranylgeranyl pyrophosphate, GGPP) used in protein geranylgeranylation reactions. Our prior studies utilizing triazole bisphosphonate-based GGDPS inhibitors (GGSIs) have revealed that these agents represent a novel strategy by which to induce cancer cell death, including multiple myeloma and pancreatic cancer. Statins inhibit the rate-limiting enzyme in the IBP and potentiate the effects of GGSIs in vitro. The in vivo effects of combination therapy with statins and GGSIs have not been determined. Here we evaluated the effects of combining VSW1198, a novel GGSI, with a statin (lovastatin or pravastatin) in CD-1 mice. Twice-weekly dosing with VSW1198 at the previously established maximally tolerated dose in combination with a statin led to hepatotoxicity, while once-weekly VSW1198-based combinations were feasible. No abnormalities in kidney, spleen, brain or skeletal muscle were observed with combination therapy. Combination therapy disrupted protein geranylgeranylation in vivo. Evaluation of hepatic isoprenoid levels revealed decreased GGPP levels in the single drug groups and undetectable GGPP levels in the combination groups. Additional studies with combinations using 50% dose-reductions of either VSW1198 or lovastatin revealed minimal hepatotoxicity with expected on-target effects of diminished GGPP levels and disruption of protein geranylgeranylation. Combination statin/GGSI therapy significantly slowed tumor growth in a myeloma xenograft model. Collectively, these studies are the first to demonstrate that combination IBP inhibitor therapy alters isoprenoid levels and disrupts protein geranylgeranylation in vivo as well as slows tumor growth in a myeloma xenograft model, thus providing the framework for future clinical exploration.

Keywords: Geranylgeranyl diphosphate synthase; Inhibitor; Isoprenoid biosynthesis; Myeloma; Statins; lovastatin (PubChem CID: 53232); pravastatin (PubChem CID: 54687).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biosynthetic Pathways / drug effects*
Biosynthetic Pathways / physiology
Cell Line, Tumor
Chemical and Drug Induced Liver Injury / metabolism
Chemical and Drug Induced Liver Injury / pathology
Diterpenes / administration & dosage*
Diterpenes / toxicity
Drug Delivery Systems / methods*
Drug Evaluation, Preclinical / methods
Drug Therapy, Combination
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / toxicity
Farnesyltranstransferase / antagonists & inhibitors
Farnesyltranstransferase / metabolism
Female
Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
Hydroxymethylglutaryl-CoA Reductase Inhibitors / toxicity
Lovastatin / administration & dosage
Lovastatin / toxicity
Mice
Mice, Inbred NOD
Mice, SCID
Pravastatin / administration & dosage
Pravastatin / toxicity
Protein Prenylation / drug effects*
Protein Prenylation / physiology
Terpenes / antagonists & inhibitors
Terpenes / metabolism*
Triazoles / administration & dosage*
Triazoles / toxicity
Xenograft Model Antitumor Assays / methods

Substances

Diterpenes
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Terpenes
Triazoles
VSW1198
Lovastatin
Farnesyltranstransferase
Pravastatin

Grants and funding

P30 CA036727/CA/NCI NIH HHS/United States