title: Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay.
abstract: Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation.
authors.affiliation: Translational Oncology Research Centre, Queen Alexandra Hospital, The Pathology Centre, Portsmouth, UK. knight.louise@googlemail.com
authors.forename: Louise A
authors.initials: LA
authors.lastname: Knight
authors.forename: Christian M
authors.initials: CM
authors.lastname: Kurbacher
authors.forename: Sharon
authors.initials: S
authors.lastname: Glaysher
authors.forename: Augusta
authors.initials: A
authors.lastname: Fernando
authors.forename: Ralf
authors.initials: R
authors.lastname: Reichelt
authors.forename: Susanne
authors.initials: S
authors.lastname: Dexel
authors.forename: Uwe
authors.initials: U
authors.lastname: Reinhold
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007093:Imidazoles; D007211:Indoles; D000077340:Fluvastatin; D000077211:Zoledronic Acid; D000255:Adenosine Triphosphate; D008798:Mevalonic Acid