Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells

Zoledronic acid, a potent nitrogen-containing bisphosphonate (NBP), has been extensively used to limit bone turnover in a various diseases including tumors. Recent clinical studies have demonstrated direct anti-cancer effects of zoledronic acid, in addition to its clinical benefits for skeletal-related events. Here we investigated the effects of 4 clinically available NBPs on human tumor cell proliferation. Our data demonstrate a potent anti-proliferative effect of zoledronic acid against glioblastoma (GBM) cell lines, breast cancer cells and GBM patient-derived lines. Zoledronic acid also effectively inhibited GBM tumor growth in xenograft mouse models. Zoledronic acid strongly stimulated autophagy but not apoptotic signals in all tested cells. Only one intermediate product of cholesterols synthesis pathway, geranylgeranyl diphosphate (GGPP) rescued cells from the cytotoxic effects of zoledronic acid. To further investigate the effect of GGPP, we knocked down RABGGTA, which encodes a subunit of the Rabgeranylgeranyltransferase protein. This knockdown induced an effect similar to zoledronic acid in cancer cell lines. These data are promising and suggested a potential for zoledronic acid as an anti-cancer agent, through its ablation of the function of Rab proteins.

• Publication year

  2016

• Venue

  OncoTarget

• Publication date

  2016-07-22

• Fields of study

  Medicine

• Identifiers
  DOI 10.18632/oncotarget.10773PMID 27462771PMCID 5295401
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

  2025cited by this paper
• miR-5100 promotes tumor growth in lung cancer by targeting Rab6.

  2015cited by this paper
• Geranylgeranyl pyrophosphate is crucial for neuronal survival but has no special role in Purkinje cell degeneration in Niemann Pick type C1 disease

  2015cited by this paper
• Genetic Characteristics of Glioblastoma: Clinical Implications of Heterogeneity

  2015influential reference
• Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs

  2014cited by this paper
• RAB7 controls melanoma progression by exploiting a lineage-specific wiring of the endolysosomal pathway.

  2014cited by this paper
• In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells

  2014cited by this paper
• High expression of RAB27A and TP53 in pancreatic cancer predicts poor survival

  2014cited by this paper
• Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study

  2013cited by this paper
• A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

  2013cited by this paper
• Development of selective, potent RabGGTase inhibitors.

  2012cited by this paper
• Zoledronic Acid Produces Antitumor Effects on Mesothelioma Through Apoptosis and S-Phase Arrest in p53-Independent and Ras prenylation-Independent Manners

  2012cited by this paper
• Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity

  2012cited by this paper
• Psoromic acid is a selective and covalent Rab-prenylation inhibitor targeting autoinhibited RabGGTase.

  2012cited by this paper
• Differential expression of Rab27A/B correlates with clinical outcome in hepatocellular carcinoma.

  2012cited by this paper
• Anticancer evidence for zoledronic acid across the cancer continuum.

  2011cited by this paper
• Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers

  2011cited by this paper
• Zoledronic Acid Enhances Vδ2 T-Lymphocyte Antitumor Response to Human Glioma Cell Lines

  2011cited by this paper
• The mevalonate pathway in C. Elegans

  2011cited by this paper
• Breast-cancer adjuvant therapy with zoledronic acid.

  2011cited by this paper
• Targeting protein prenylation for cancer therapy

  2011cited by this paper
• Anti-tumour activity of bisphosphonates in preclinical models of breast cancer

  2010cited by this paper
• Dysregulation of the mevalonate pathway promotes transformation

  2010cited by this paper
• Bisphosphonate Use in Patients with Lung Cancer and Bone Metastases: Recommendations of a European Expert Panel

  2009cited by this paper
• Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.

  2009cited by this paper
• Malignant gliomas in adults.

  2008cited by this paper
• Enhanced Expression of Rab27A Gene by Breast Cancer Cells Promoting Invasiveness and the Metastasis Potential by Secretion of Insulin-Like Growth Factor-II

  2008cited by this paper
• Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients

  2007cited by this paper
• Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases

  2007cited by this paper
• Brain cholesterol turnover required for geranylgeraniol production and learning in mice.

  2006cited by this paper
• The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs

  2006cited by this paper
• Inhibitors of protein: geranylgeranyl transferases.

  2006cited by this paper
• Conversion of protein farnesyltransferase to a geranylgeranyltransferase.

  2006cited by this paper
• Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells

  2006cited by this paper
• Zoledronic acid for the treatment of bone metastases in patients with breast cancer and other solid tumors.

  2003cited by this paper
• The potential role of bisphosphonates in prostate cancer

  2002cited by this paper
• Late endosome motility depends on lipids via the small GTPase Rab7

  2002cited by this paper
• Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa).

  2002cited by this paper
• The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking.

  2002cited by this paper
• Rab27a Regulates the Peripheral Distribution of Melanosomes in Melanocytes

  2001cited by this paper
• Bisphosphonate treatment inhibits the growth of prostate cancer cells.

  2001cited by this paper
• Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.

  2001cited by this paper
• The Rab GTPase family

  2001cited by this paper
• Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis.

  2000cited by this paper
• Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis.

  1999cited by this paper
• Interaction of a Golgi-associated kinesin-like protein with Rab6.

  1998cited by this paper
• Protein prenylation: molecular mechanisms and functional consequences.

  1996cited by this paper
• Geranylgeraniol is a potent inducer of apoptosis in tumor cells.

  1995cited by this paper
• Preclinical pharmacology of CGP 42′446, a new, potent, heterocyclic bisphosphonate compound

  1994cited by this paper
• Protein farnesyltransferase and geranylgeranyltransferase share a common α subunit

  1991cited by this paper
• Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit.

  1991cited by this paper

• The Complexity of Malignant Glioma Treatment

  2025cites this paper
• Biomolecular fingerprints of the effect of zoledronic acid on prostate cancer stem cells: Comparison of 2D and 3D cell culture models.

  2024cites this paper
• Role of bisphosphonates in hypertrophic osteoarthropathy: a systematic review

  2024cites this paper
• Geranylgeranyl diphosphate synthase inhibition impairs osteoclast differentiation, morphology, and resorptive activity

  2024cites this paper
• Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

  2023cites this paper
• Mitochondria in oral cancer stem cells: Unraveling the potential drug targets for new and old drugs.

  2023cites this paper
• Abstracts from the Bone Research Society Annual Meeting, April 13–15, 2023, Liverpool, UK

  2023cites this paper
• Pharmacogenetics of Osteoporosis: A Pathway Analysis of the Genetic Influence on the Effects of Antiresorptive Drugs

  2022cites this paper
• The Two-Faced Role of Autophagy in Endometrial Cancer

  2022cites this paper
• Integrating Single-Cell Transcriptome and Network Analysis to Characterize the Therapeutic Response of Chronic Myeloid Leukemia

  2022cites this paper
• Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer

  2021cites this paper
• Phosphonate and Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthases: A Structure-Guided Perspective

  2021cites this paper
• Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme

  2020cites this paper
• Potentiating bisphosphonate-based coordination complexes to treat osteolytic metastases.

  2020cites this paper
• A remarkable in vitro cytotoxic, cell cycle arresting and proapoptotic characteristics of low-dose mixed micellar simvastatin combined with alendronate sodium

  2020cites this paper
• Zoledronic acid impairs oral cancer stem cells by reducing CCL3.

  2020cites this paper
• Zoledronic acid effects the cell cycle signalling AURKA gene in MDA MB231 breast cancer cells

  2019cites this paper
• Bone-Bound Bisphosphonates Inhibit Proliferation of Breast Cancer Cells

  2019cites this paper
• Zoledronic Acid Inhibits the RhoA-mediated Amoeboid Motility of Prostate Cancer Cells.

  2019cites this paper
• Interacting Cancer Machineries: Cell Signaling, Lipid Metabolism, and Epigenetics.

  2018cites this paper
• The role of dental care providers in the management of patients prescribed bisphosphonates: brief clinical guidance.

  2018cites this paper
• An eight‐long noncoding RNA expression signature for colorectal cancer patients’ prognosis

  2018cites this paper
• Regulation of coenzyme Q biosynthesis through nutritional and pharmacological interventions

  2017influential citation