Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay |
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Authors: | Louise A Knight Christian M Kurbacher Sharon Glaysher Augusta Fernando Ralf Reichelt Susanne Dexel Uwe Reinhold and Ian A Cree |
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Institution: | (1) The Pathology Centre, Translational Oncology Research Centre, Queen Alexandra Hospital, PO6 3LY Portsmouth, UK;(2) L.a.n.c.e. Inc, Friedensplatz 16, 53111 Bonn, Germany;(3) Department of Dermatology, Medical Center Bonn-Friedenplatz, Friedensplatz 16, 53111 Bonn, Germany |
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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. |
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