title: Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells.
abstract: 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.
authors.affiliation: Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu Province 221009, China.
authors.forename: Peiying
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.affiliation: Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Pingle
authors.affiliation: Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA.|Institute of Engineering in Medicine, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Dayu
authors.initials: D
authors.lastname: Teng
authors.affiliation: Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA.|Institute of Engineering in Medicine, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Key Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Translational Neuro-Oncology and Neurotherapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D061986:MCF-7 Cells; D051379:Mice; D009368:Neoplasm Transplantation; D009584:Nitrogen / Q000737:chemistry*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D009584:Nitrogen
keywords: autophagy; bisphosphonates; cancer therapy; glioblastoma; zoledronic acid