ArticleCell death & disease2017
Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation.
Article in Cell death & disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia (AML).Research square · 2025Article
- Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies.International journal of molecular sciences · 2025Article
- Leveraging altered lipid metabolism in treating B cell malignancies.Progress in lipid research · 2024Review
- Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.Cancer cell international · 2024Article
- Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy.Molecular cancer therapeutics · 2024Review
- Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target.Clinical and translational medicine · 2023Review
- Biosynthesis of anticancer phytochemical compounds and their chemistry.Frontiers in pharmacology · 2023Review
- Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma.International journal of molecular sciences · 2022Review
- Characterization of Fecal Microbiomes of Osteoporotic Patients in Korea.Polish journal of microbiology · 2022Article
- Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma.Metabolites · 2022Article
- RhoA: a dubious molecule in cardiac pathophysiology.Journal of biomedical science · 2021Review
- Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition.Cell death & disease · 2019Article
- The role of cholesterol metabolism in leukemia.Blood science (Baltimore, Md.) · 2019Review
- Preclinical investigation of a potent geranylgeranyl diphosphate synthase inhibitor.Investigational new drugs · 2018Article
- Serial Changes in Thyroid Hormones with Oral or Intravenous Bisphosphonates.Indian journal of endocrinology and metabolismArticle
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bisphosphonates are diphosphate analogs that inhibit the intermediate enzymes of the mevalonate pathway. Here, we compared the effects of a farnesyl diphosphate synthase inhibitor, zoledronate, and a geranylgeranyl diphosphate synthase (GGDPS) inhibitor, digeranyl bisphosphonate (DGBP), on lymphocytic leukemia cell proliferation and apoptosis. Both zoledronate and DGBP inhibited proliferation with DGBP doing so more potently. DGBP was markedly less toxic than zoledronate toward the viability of healthy human peripheral blood mononuclear cells. Addition of GGPP, but not farnesyl diphosphate (FPP), prevented the anti-proliferative effects of DGBP. Both GGPP and FPP partially rescued the effects of zoledronate. Co-treatment with DGBP and zoledronate was antagonistic. To further assess the effects of the bisphosphonates, we analyzed annexin V and propidium iodide staining via flow cytometry and found that DGBP induced apoptosis more potently than zoledronate. Western blots show that DGBP treatment altered expression and membrane affinity of some but not all geranylgeranylated small GTPases, activated caspases and increased ERK phosphorylation. Importantly, the anti-proliferative effects of DGBP were blocked by treatment with a caspase inhibitor and by treatment with a MEK inhibitor. Together, our findings indicate that DGBP is a more potent and selective compound than zoledronate in inducing apoptosis mediated through pathways that include caspases and MEK/ERK. These findings support the further development of GGDPS inhibitors as anticancer therapeutics.
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