title: Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop.
abstract: New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pandyra
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mullen
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Manpreet
authors.initials: M
authors.lastname: Kalkat
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Yu
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Janice T
authors.initials: JT
authors.lastname: Pong
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.affiliation: Institute of Immunology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. lpenn@uhnres.utoronto.ca.
authors.forename: Linda Z
authors.initials: LZ
authors.lastname: Penn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004176:Dipyridamole; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051782:Sterol Regulatory Element Binding Protein 2; D004176:Dipyridamole; D006904:Hydroxymethylglutaryl-CoA Synthase; D008798:Mevalonic Acid