Digeranyl bisphosphonate

Digeranyl bisphosphonate is a lipophilic geranylgeranyl diphosphate synthase (GGDPS) inhibitor. Digeranyl bisphosphonate competitively binds to the GGDPS active site. Digeranyl bisphosphonate attenuates Rac1 mitochondrial import, mitochondrial oxidative stress, ERK phosphorylation, and caspase activation. Digeranyl bisphosphonate induces apoptosis or autophagy. Digeranyl bisphosphonate can be used in studies related to pulmonary fibrosis, lymphoid leukemia, prostate cancer metastasis, and multiple myeloma^[1-4].

In vitro, treatment of Molt-4 cells with 15-30µM Digeranyl bisphosphonate for 72 hours, or treatment of Jurkat cells with 30µM or 81µM Digeranyl bisphosphonate for 72 hours, dose-dependently inhibited cell proliferation and increased the proportion of late apoptotic cells^[5]. Treatment of LNCaP cells with 30µM Digeranyl bisphosphonate for 48 hours to 28 days reduced mRNA expression of FKBP5, KLK3, NKX3-1, and TMPRSS2. Treatment of LNCaP, 22Rv1, and C4-2B4 cells with Digeranyl bisphosphonate for 72 hours reduced AR nuclear localization^[6]. Treatment of MDA-MB-231 human breast cancer cells with 25µM Digeranyl bisphosphonate for 24 hours reduced membrane-associated RhoA, increased cytosolic RhoA, and increased GTP-bound RhoA. Treatment of MDA-MB-231 cells with 25µM Digeranyl bisphosphonate for 24 hours or continuously for up to 71 hours inhibited cell transwell migration and time-dependently reduced cell migration speed^[7].

In vivo, C57BL/6 wild-type mice received subcutaneous implantation of osmotic pumps containing 0.2mg/kg Digeranyl bisphosphonate. The next day, mice received intratracheal administration of 100μg Chrysotile or 1.3-2.0U/kg Bleomycin Sulfate. Continuous drug delivery lasted 21 days. Digeranyl bisphosphonate reduced mitochondrial Rac1 content and increased cytosolic Rac1 in alveolar macrophages. Digeranyl bisphosphonate reduced reactive oxygen species generation rate in mitochondrial. Seven days after Bleomycin administration, osmotic pumps containing 0.2mg/kg Digeranyl bisphosphonate were implanted for another 21 days. Digeranyl bisphosphonate reduced lung hydroxyproline content, significantly decreased collagen plaque area, and prevented pulmonary fibrosis progression^[8]. Starting 5 days before bile duct ligation and cholecystectomy (BDLC), C57BL/6J mice received subcutaneous injections of 0.15mg/kg Digeranyl bisphosphonate twice daily for 5 consecutive days. Mice then underwent BDLC and were sacrificed on day 5 after surgery. Digeranyl bisphosphonate improved overall survival rate at 5 days after surgery, reduced serum ALT, total bilirubin, and total bile acid levels, decreased liver necrotic area, and alleviated acute obstructive cholestatic liver injury^[9]. Metabolically unhealthy obesity (MUO) model C57BL/6J mice received subcutaneous injections of 0.15mg/kg Digeranyl bisphosphonate for 5 consecutive days. Digeranyl bisphosphonate improved glucose tolerance and insulin sensitivity, reduced plasma glucose and insulin concentrations, and alleviated hepatic lipid deposition. Body weight and liver weight were not changed. Serum ALT and AST levels were elevated^[10].

References:

[1] Wiemer AJ, Tong H, Swanson KM, et al. Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem Biophys Res Commun. 2007 Feb 23;353(4):921-5.

[2] Wasko BM, Dudakovic A, Hohl RJ. Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate. J Pharmacol Exp Ther. 2011 May;337(2):540-6.

[3] Weivoda MM, Hohl RJ. The effects of direct inhibition of geranylgeranyl pyrophosphate synthase on osteoblast differentiation. J Cell Biochem. 2011 Jun;112(6):1506-13.

[4] Haney SL, Wills VS, Wiemer DF, et al. Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors. Molecules. 2017 May 27;22(6):886.

[5] Agabiti SS, Li J, Wiemer AJ. Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation. Cell Death Dis. 2017;8(3):e2678.

[6] Weissenrieder JS, Reilly JE, Neighbors JD, et al. Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models. Prostate. 2018;1-10. 

[7] Dudakovic A, Tong H, Hohl RJ. Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration. Invest New Drugs. 2011;29(5):912-920.

[8] Osborn-Heaford HL, Murthy S, Gu L, et al. Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. Free Radic Biol Med. 2015 Sep;86:47-56.

[9] Jia WJ, Tang QL, Jiang S, et al. Conditional loss of geranylgeranyl diphosphate synthase alleviates acute obstructive cholestatic liver injury by regulating hepatic bile acid metabolism. FEBS J. 2020;287(1):1-18.

[10] Zhao Y, Nie HY, Jiang S, et al. Geranylgeranyl Pyrophosphate Promotes Hepatic Lipid Accumulation by Prenylation of Perilipin4. Cell Mol Gastroenterol Hepatol. 2025;19:101546.