{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:39:54Z","timestamp":1782275994187,"version":"3.54.5"},"reference-count":106,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA258621"],"award-info":[{"award-number":["R01 CA258621"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA036727"],"award-info":[{"award-number":["P30 CA036727"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM) is a plasma cell malignancy for which there is currently no cure. While treatment options for MM have expanded over the last two decades, all patients will eventually become resistant to current therapies. Thus, there is an urgent need for novel therapeutic strategies to treat MM. The isoprenoid biosynthetic pathway (IBP) is responsible for the post-translational modification of proteins belonging to the Ras small GTPase superfamily, such as Ras, Rho and Rab family members. Given the important roles these GTPase proteins play in various cellular processes, there is significant interest in the development of inhibitors that disturb their prenylation and consequently their activity in MM cells. Numerous preclinical studies have demonstrated that IBP inhibitors have anti-MM effects, including the induction of apoptosis in MM cells and inhibition of osteoclast activity. Some IBP inhibitors have made their way into the clinic. For instance, nitrogenous bisphosphonates are routinely prescribed for the management MM bone disease. Other IBP inhibitors, including statins and farnesyltransferase inhibitors, have been evaluated in clinical trials for MM, while there is substantial preclinical investigation into geranylgeranyl diphosphate synthase inhibitors. Here we discuss recent advances in the development of IBP inhibitors, assess their mechanism of action and evaluate their potential as anti-MM agents.<\/jats:p>","DOI":"10.3390\/ijms24010111","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T06:11:24Z","timestamp":1671603084000},"page":"111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma"],"prefix":"10.3390","volume":"24","author":[{"given":"Staci L.","family":"Haney","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, 986840 Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-5635","authenticated-orcid":false,"given":"Sarah A.","family":"Holstein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, 986840 Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3109\/10428194.2014.907890","article-title":"The role of P-glycoprotein in drug resistance in multiple myeloma","volume":"56","author":"Abraham","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2147\/ITT.S306103","article-title":"Immunotherapy of Multiple Myeloma: Promise and Challenges","volume":"10","author":"Abramson","year":"2021","journal-title":"ImmunoTargets Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5289","DOI":"10.1074\/jbc.271.10.5289","article-title":"Protein prenyltransferases","volume":"271","author":"Casey","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/s41594-019-0249-3","article-title":"GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase","volume":"26","author":"Kuchay","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e104120","DOI":"10.15252\/embj.2019104120","article-title":"A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus","volume":"39","author":"Shirakawa","year":"2020","journal-title":"EMBO J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/nrc3151","article-title":"Targeting protein prenylation for cancer therapy","volume":"11","author":"Berndt","year":"2011","journal-title":"Nat. Reviews. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1038\/emboj.2008.164","article-title":"Structures of RabGGTase-substrate\/product complexes provide insights into the evolution of protein prenylation","volume":"27","author":"Guo","year":"2008","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11963","DOI":"10.1073\/pnas.91.25.11963","article-title":"Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A","volume":"91","author":"Farnsworth","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0076-6879(01)29063-6","article-title":"4-Prenylation of Rab Proteins in Vitro by Geranylgeranyltransferases","volume":"Volume 329","author":"Balch","year":"2001","journal-title":"Methods in Enzymology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1091\/mbc.e02-10-0639","article-title":"Membrane targeting of Rab GTPases is influenced by the prenylation motif","volume":"14","author":"Gomes","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1073\/pnas.87.8.3042","article-title":"Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation","volume":"87","author":"Jackson","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.bone.2005.04.021","article-title":"Phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase disrupt the prenylation and membrane localization of Rab proteins in osteoclasts in vitro and in vivo","volume":"37","author":"Coxon","year":"2005","journal-title":"Bone"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e29710","DOI":"10.4161\/sgtp.29710","article-title":"Rho GTPases: Masters of cell migration","volume":"5","author":"Sadok","year":"2014","journal-title":"Small GTPases"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrm3153","article-title":"The \u2018invisible hand\u2019: Regulation of RHO GTPases by RHOGDIs","volume":"12","author":"Boulter","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1242\/jcs.01660","article-title":"The Ras superfamily at a glance","volume":"118","author":"Wennerberg","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/0005-2760(83)90154-6","article-title":"Regulation of hepatic receptor-dependent degradation of LDL by mevinolin in rabbits with hypercholesterolemia induced by a wheat starch-casein diet","volume":"754","author":"Chao","year":"1983","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1073\/pnas.80.13.4124","article-title":"Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes","volume":"80","author":"Bilheimer","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1253\/circj.CJ-10-0110","article-title":"Pleiotropic Effects of Statins\u2013Basic Research and Clinical Perspectives","volume":"74","author":"Zhou","year":"2010","journal-title":"Circ. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3524","DOI":"10.1158\/1078-0432.CCR-12-0489","article-title":"Novel aspects of mevalonate pathway inhibitors as antitumor agents","volume":"18","author":"Thurnher","year":"2012","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1093\/carcin\/bgi036","article-title":"Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells","volume":"26","author":"Cafforio","year":"2005","journal-title":"Carcinogenesis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1177\/108155890405200534","article-title":"Simvastatin induces death of multiple myeloma cell lines","volume":"52","author":"Gronich","year":"2004","journal-title":"J. Investig. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4415","DOI":"10.1182\/blood-2006-09-047076","article-title":"Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation","volume":"109","author":"Dai","year":"2007","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.leukres.2010.08.008","article-title":"Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells","volume":"35","author":"Holstein","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1600-0609.2007.00902.x","article-title":"First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma","volume":"79","author":"Schmidmaier","year":"2007","journal-title":"Eur. J. Haematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/hon.869","article-title":"A phase II clinical trial does not show that high dose simvastatin has beneficial effect on markers of bone turnover in multiple myeloma","volume":"27","author":"Sondergaard","year":"2009","journal-title":"Hematol. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s00277-011-1276-2","article-title":"Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma","volume":"90","author":"Hus","year":"2011","journal-title":"Ann. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/bcr414","article-title":"The role of bisphosphonates in breast cancer: Development of bisphosphonates","volume":"4","author":"Fleisch","year":"2001","journal-title":"Breast Cancer Res."},{"key":"ref_28","first-page":"CD003188","article-title":"Bisphosphonates in multiple myeloma: An updated network meta-analysis","volume":"12","author":"Mhaskar","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1073\/pnas.96.1.133","article-title":"Alendronate mechanism of action: Geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro","volume":"96","author":"Fisher","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1016\/j.bmc.2007.01.002","article-title":"Synthesis of fluorescently tagged isoprenoid bisphosphonates that inhibit protein geranylgeranylation","volume":"15","author":"Maalouf","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1359\/jbmr.2000.15.8.1467","article-title":"Protein geranylgeranylation is required for osteoclast formation, function, and survival: Inhibition by bisphosphonates and GGTI-298","volume":"15","author":"Coxon","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1056\/NEJM198002073020602","article-title":"Effects of dichloromethylene diphosphonate on skeletal mobilization of calcium in multiple myeloma","volume":"302","author":"Siris","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1016\/S0140-6736(10)62051-X","article-title":"First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial","volume":"376","author":"Morgan","year":"2010","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5374","DOI":"10.1182\/blood-2011-11-392522","article-title":"Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: The Medical Research Council Myeloma IX Trial","volume":"119","author":"Morgan","year":"2012","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1158\/1078-0432.CCR-14-3214","article-title":"Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?","volume":"21","author":"Cox","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"John, L., Krauth, M.T., Podar, K., and Raab, M.-S. (2021). Pathway-Directed Therapy in Multiple Myeloma. Cancers, 13.","DOI":"10.3390\/cancers13071668"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1038\/leu.2008.142","article-title":"Clinical and biological significance of RAS mutations in multiple myeloma","volume":"22","author":"Chng","year":"2008","journal-title":"Leukemia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1182\/blood.V88.7.2699.bloodjournal8872699","article-title":"Activating Mutations of N- and K-ras in Multiple Myeloma Show Different Clinical Associations: Analysis of the Eastern Cooperative Oncology Group Phase III Trial","volume":"88","author":"Liu","year":"1996","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1177\/107327480301000505","article-title":"Farnesyltransferase inhibitors and their role in the treatment of multiple myeloma","volume":"10","author":"Santucci","year":"2003","journal-title":"Cancer Control"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1677\/erc.0.0080227","article-title":"Farnesyl transferase inhibitors--a novel therapy for breast cancer","volume":"8","author":"Johnston","year":"2001","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4527","DOI":"10.1182\/blood-2002-11-3359","article-title":"Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting","volume":"102","author":"Kurzrock","year":"2003","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1182\/blood.V97.11.3361","article-title":"Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase 1 clinical-laboratory correlative trial","volume":"97","author":"Karp","year":"2001","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.2174\/1568026033452050","article-title":"Farnesyl protein transferase inhibitor ZARNESTRA R115777-history of a discovery","volume":"3","author":"Venet","year":"2003","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1182\/blood-2003-08-2764","article-title":"Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic\/tumor survival pathways in patients with advanced multiple myeloma","volume":"103","author":"Alsina","year":"2004","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s12035-010-8144-2","article-title":"RHO GTPase signaling for axon extension: Is prenylation important?","volume":"42","author":"Samuel","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/21541248.2016.1232583","article-title":"Rho GTPases: Regulation and roles in cancer cell biology","volume":"7","author":"Haga","year":"2016","journal-title":"Small GTPases"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7605","DOI":"10.12659\/MSM.915998","article-title":"The Effect of Ras Homolog C\/Rho-Associated Coiled-Protein Kinase (Rho\/ROCK) Signaling Pathways on Proliferation and Apoptosis of Human Myeloma Cells","volume":"25","author":"Feng","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s11523-019-00661-5","article-title":"A Phase I Study of GGTI-2418 (Geranylgeranyl Transferase I Inhibitor) in Patients with Advanced Solid Tumors","volume":"14","author":"Karasic","year":"2019","journal-title":"Target. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"48213","DOI":"10.1074\/jbc.M106473200","article-title":"Identification of a novel phosphonocarboxylate inhibitor of Rab geranylgeranyl transferase that specifically prevents Rab prenylation in osteoclasts and macrophages","volume":"276","author":"Coxon","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1002\/ijc.21977","article-title":"Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells","volume":"119","author":"Roelofs","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.bbrc.2008.09.157","article-title":"Geranylgeranyl transferase type II inhibition prevents myeloma bone disease","volume":"377","author":"Lawson","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8781","DOI":"10.1021\/acs.jmedchem.7b00811","article-title":"Identification of the Privileged Position in the Imidazo [1,2-a]pyridine Ring of Phosphonocarboxylates for Development of Rab Geranylgeranyl Transferase (RGGT) Inhibitors","volume":"60","author":"Kazmierczak","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1016\/j.bmcl.2015.04.021","article-title":"N-Oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation","volume":"25","author":"Zhou","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"126757","DOI":"10.1016\/j.bmcl.2019.126757","article-title":"Novel benzimidazole phosphonates as potential inhibitors of protein prenylation","volume":"29","author":"Bhuiyan","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.bmcl.2012.11.089","article-title":"Triazole-based inhibitors of geranylgeranyltransferase II","volume":"23","author":"Zhou","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8330","DOI":"10.1021\/jm300624s","article-title":"Development of selective, potent RabGGTase inhibitors","volume":"55","author":"Stigter","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1021\/acschembio.6b00386","article-title":"Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase","volume":"11","author":"Cromm","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1021\/acsmedchemlett.5b00334","article-title":"Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase","volume":"6","author":"Wills","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9438","DOI":"10.1021\/acs.joc.6b01693","article-title":"Stereoselective synthesis of homoneryl and homogeranyl triazole bisphosphonates","volume":"81","author":"Matthiesen","year":"2016","journal-title":"J. Org. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1124\/mol.116.107326","article-title":"Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase","volume":"91","author":"Allen","year":"2017","journal-title":"Mol. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.bmc.2017.10.023","article-title":"\u03b1-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors","volume":"26","author":"Matthiesen","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1021\/acs.jmedchem.1c01913","article-title":"Synthesis and Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase","volume":"65","author":"Lee","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1182\/blood-2003-03-0970","article-title":"Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels","volume":"102","author":"Kamphuis","year":"2003","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.bbrc.2008.07.012","article-title":"HMG-CoA reductase inhibitor simvastatin overcomes bortezomib-induced apoptosis resistance by disrupting a geranylgeranyl pyrophosphate-dependent survival pathway","volume":"374","author":"Fuchs","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.leukres.2009.06.035","article-title":"Differential activities of thalidomide and isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells","volume":"34","author":"Holstein","year":"2010","journal-title":"Leuk. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.semcdb.2007.09.003","article-title":"The endoplasmic reticulum and the unfolded protein response","volume":"18","author":"Malhotra","year":"2007","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1182\/blood-2005-08-3531","article-title":"Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells","volume":"107","author":"Obeng","year":"2006","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1124\/jpet.119.258624","article-title":"In Vivo Evaluation of Isoprenoid Triazole Bisphosphonate Inhibitors of Geranylgeranyl Diphosphate Synthase: Impact of Olefin Stereochemistry on Toxicity and Biodistribution","volume":"371","author":"Haney","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5308","DOI":"10.1038\/s41388-019-0794-6","article-title":"Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma","volume":"38","author":"Haney","year":"2019","journal-title":"Oncogene"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Haney, S.L., Feng, D., Chhonker, Y.S., Varney, M.L., Williams, J.T., Smith, L.M., Ford, J.B., Murry, D.J., and Holstein, S.A. (2022). Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma. Drug Dev. Res.","DOI":"10.1002\/ddr.22012"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e2678","DOI":"10.1038\/cddis.2017.101","article-title":"Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation","volume":"8","author":"Agabiti","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.bone.2009.08.010","article-title":"The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro","volume":"45","author":"Mitrofan","year":"2009","journal-title":"Bone"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S8756-3282(98)00120-3","article-title":"Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: Structure-activity relationships","volume":"23","author":"Ebetino","year":"1998","journal-title":"Bone"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.biopha.2015.12.017","article-title":"Statins inhibited the MIP-1alpha expression via inhibition of Ras\/ERK and Ras\/Akt pathways in myeloma cells","volume":"78","author":"Tsubaki","year":"2016","journal-title":"Biomed Pharm."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1111\/j.1365-2141.2005.05696.x","article-title":"Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells","volume":"130","author":"Morgan","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/sj.leu.2402832","article-title":"The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells","volume":"17","author":"Bolick","year":"2003","journal-title":"Leukemia"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ejphar.2011.09.031","article-title":"Involvement of Chk1-Cdc25A-cyclin A\/CDK2 pathway in simvastatin induced S-phase cell cycle arrest and apoptosis in multiple myeloma cells","volume":"670","author":"Tu","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.leukres.2008.06.001","article-title":"Inhibition of the mevalonate pathway potentiates the effects of lenalidomide in myeloma","volume":"33","author":"Bloem","year":"2009","journal-title":"Leuk. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.leukres.2013.01.022","article-title":"Induction of apoptosis in multiple myeloma cells by a statin-thalidomide combination can be enhanced by p38 MAPK inhibition","volume":"37","author":"Zdzisinska","year":"2013","journal-title":"Leuk. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1158\/1078-0432.CCR-05-1792","article-title":"Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia","volume":"12","author":"Yanamandra","year":"2006","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5285","DOI":"10.1182\/blood-2010-03-272393","article-title":"Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes","volume":"116","author":"David","year":"2010","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/s41375-020-0962-2","article-title":"The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma","volume":"35","author":"Longo","year":"2021","journal-title":"Leukemia"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40164-022-00261-6","article-title":"Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma","volume":"11","author":"Haney","year":"2022","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4787","DOI":"10.1182\/blood-2009-07-230508","article-title":"Exploiting the mevalonate pathway to distinguish statin-sensitive multiple myeloma","volume":"115","author":"Clendening","year":"2010","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/ijc.24758","article-title":"The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation","volume":"126","author":"Guenther","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1021\/acs.jmedchem.8b00886","article-title":"Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors","volume":"61","author":"Lacbay","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"105528","DOI":"10.1016\/j.phrs.2021.105528","article-title":"In vivo evaluation of combination therapy targeting the isoprenoid biosynthetic pathway","volume":"167","author":"Haney","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1182\/blood-2008-05-159392","article-title":"Interruption of the Ras\/MEK\/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells","volume":"112","author":"Dai","year":"2008","journal-title":"Blood"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1002\/j.1552-4604.1990.tb01856.x","article-title":"Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin","volume":"30","author":"Pan","year":"1990","journal-title":"J. Clin. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"19937","DOI":"10.1016\/S0021-9258(17)45464-0","article-title":"Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis","volume":"265","author":"Sinensky","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_92","first-page":"483","article-title":"Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer","volume":"2","author":"Thibault","year":"1996","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00280-005-0013-8","article-title":"Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies","volume":"57","author":"Holstein","year":"2006","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4008","DOI":"10.1200\/JCO.2016.68.3482","article-title":"Statins Are Associated With Reduced Mortality in Multiple Myeloma","volume":"34","author":"Sanfilippo","year":"2016","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1002\/ajh.25778","article-title":"Statin use is associated with improved survival in multiple myeloma: A Swedish population-based study of 4315 patients","volume":"95","author":"Branvall","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e399","DOI":"10.1016\/j.clml.2020.02.011","article-title":"Receipt of Statins Is Associated With Lower Risk of Multiple Myeloma: Systematic Review and Meta-analysis","volume":"20","author":"Ponvilawan","year":"2020","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.3109\/10428194.2015.1094693","article-title":"Risk of multiple myeloma in a case-spouse study","volume":"57","author":"Andreotti","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/ijc.30745","article-title":"Statin use and risk of multiple myeloma: An analysis from the cancer research network","volume":"141","author":"Epstein","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.pharmthera.2015.11.008","article-title":"Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials","volume":"158","author":"Anguille","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.3892\/or.2011.1152","article-title":"Zoledronic acid, a third-generation bisphosphonate, inhibits cellular growth and induces apoptosis in oral carcinoma cell lines","volume":"25","author":"Tamura","year":"2011","journal-title":"Oncol. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.taap.2012.01.024","article-title":"Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529\/ONO-5920-induced blockade of the Ras\/MEK\/ERK and Ras\/PI3K\/Akt pathway","volume":"259","author":"Tsubaki","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.bone.2010.09.035","article-title":"Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase","volume":"48","author":"Stresing","year":"2011","journal-title":"Bone"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/sj.leu.2403693","article-title":"Effector \u03b3\u03b4 T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma","volume":"19","author":"Mariani","year":"2005","journal-title":"Leukemia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1158\/1535-7163.179.3.2","article-title":"R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways","volume":"3","author":"Beaupre","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_105","first-page":"747","article-title":"Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I","volume":"1","author":"Lobell","year":"2002","journal-title":"Mol. Cancer Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1021\/jm020587n","article-title":"Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents","volume":"46","author":"deSolms","year":"2003","journal-title":"J. Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:45:25Z","timestamp":1760147125000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,21]]},"references-count":106,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010111"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010111","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,21]]}}}