(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Ovarian-Neoplasms

We previously observed an association between ovarian cancer outcome and statin use and hypothesized lipoproteins have direct effects on ovarian cancer proliferation. Here we investigate the direct effects of low density lipoprotein (LDL) and oxidized LDL (oxLDL) on proliferation and the inhibitory effects of fluvastatin and a liver X receptor (LXR) agonist.. The effects of LDL, oxLDL, the LXR agonist TO901317, fluvastatin and cisplatin on cellular proliferation were determined using MTT assays. LXR pathway proteins were assayed by immunoblotting. Cytokine expression was determined by antibody array.. Concentrations of oxLDL as small as 0.1 microg/ml stimulated CAOV3 and SKOV3 proliferation, while LDL had no effect. TO901317 inhibited the proliferation of CAOV3, OVCAR3 and SKOV3 cells stimulated by oxLDL. Fluvastatin inhibited oxLDL mediated proliferation of CAOV3 and SKOV3. Cardiotrophin 1 (CT-1) was mitogenic to CAOV3 and SKOV3, was induced by oxLDL, and was reversed by TO901317. OxLDL increased cisplatin IC50s by 3.8 microM and > 60 microM for CAOV3 and SKOV3 cells, respectively. The LXR pathway proteins CD36, LXR, and ABCA1 were expressed in eight ovarian carcinoma cell lines (A2780, CAOV3, CP70, CSOC882, ES2, OVCAR3, SKOV3).. OxLDL reduced ovarian carcinoma cell chemosensitivity and stimulated proliferation. These effects were reversed by LXR agonist or fluvastatin. The LXR agonist also inhibited expression of the ovarian cancer mitogen CT-1. These observations suggest a biologic mechanism for our clinical finding that ovarian cancer survival is associated with statin use. Targeting LXR and statin use may have a therapeutic role in ovarian cancer.

Topics: Cell Growth Processes; Cell Line, Tumor; Drug Interactions; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydrocarbons, Fluorinated; Indoles; Ligands; Lipoproteins, LDL; Liver X Receptors; Orphan Nuclear Receptors; Ovarian Neoplasms; Sulfonamides

Statin therapy has been associated with prolonged survival in patients with ovarian cancer. We hypothesized that statins have a cytotoxic effect and that the combination of fluvastatin and cisplatin inhibits cellular proliferation in epithelial ovarian cancer cells.. Fluvastatin and cisplatin were examined in CAOV3 and SKOV3 human ovarian cancer cell lines. Cellular proliferation was assessed using MTT assays. Annexin V/propidium iodide (PI) staining was used to discriminate between early and late apoptosis, bromodeoxyuridine and PI staining for cell cycle profiling, and Western blotting for protein expression analysis. Synergy was determined using isobologram analysis.. Treatment with combination fluvastatin and cisplatin at multiple doses resulted in significantly greater inhibition of proliferation compared to either drug alone. When examining equipotent combinations of fluvastatin and cisplatin to determine potential synergy, a combination index (CI) of 0.66 was identified for CAOV3 cells and a CI of 0.24 for SKOV3 cells indicating synergy. Combination fluvastatin and cisplatin resulted in G2/M arrest, and a significant increase in early apoptotic cells compared to fluvastatin or cisplatin alone. Moreover, supplementation of farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) demonstrated that GGPP rather than FPP was able to overcome fluvastatin-induced cytotoxicity. Finally, the two-drug combination impaired the expression and modification status of proteins of the Ras pathway.. These data demonstrate the synergistic cytotoxicity of fluvastatin and cisplatin, through premature apoptosis and cell cycle arrest, with concomitant dysregulation of Ras pathway proteins. Our studies support a plausible therapeutic role for statins in the adjuvant treatment of ovarian cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cisplatin; Drug Synergism; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Ovarian Neoplasms; Prenylation; ras Proteins; Signal Transduction

Statins, prescribed for decades to control cholesterol, have more recently been shown to have promising anticancer activity. Statins induce tumor-selective apoptosis by inhibiting the mevalonate (MVA) pathway. In addition, we have recently demonstrated that lovastatin modulates drug accumulation in a MVA-independent manner in multidrug-resistant (MDR) tumor cells overexpressing the P-glycoprotein (P-gp) multidrug transporter. P-gp-mediated drug efflux can contribute to chemotherapy failure. However, direct statin-mediated inhibition of P-gp in human MDR tumor cells at clinically achievable concentrations remains unexplored. An understanding of these interactions is crucial, both to appreciate differences in the anticancer potential of different statins and to safely and effectively integrate statins into traditional chemotherapy regimens that include P-gp substrates. Here we evaluate interactions between 4 statins (lovastatin, atorvastatin, fluvastatin and rosuvastatin) and P-gp, at both the molecular level using purified P-gp and at the cellular level using human MDR tumor cells. Lovastatin bound directly to purified P-gp with high affinity and increased doxorubicin accumulation in MDR tumor cells, potentiating DNA damage, growth arrest and apoptosis. By contrast, while atorvastatin inhibited substrate transport by purified P-gp in proteoliposomes, it had no effect on doxorubicin transport in MDR tumor cells. Finally, fluvastatin and rosuvastatin only interacted with P-gp in vitro at high concentrations and did not inhibit doxorubicin transport in MDR cells. These differential interactions should be considered when combining statins with traditional chemotherapeutic drugs.

Topics: Antineoplastic Agents; Apoptosis; Atorvastatin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Proliferation; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fatty Acids, Monounsaturated; Female; Fluorobenzenes; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Ovarian Neoplasms; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Sulfonamides; Tumor Cells, Cultured

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.

Topics: Adenosine Triphosphate; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diphosphonates; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Imidazoles; Indoles; Mevalonic Acid; Middle Aged; Ovarian Neoplasms; Signal Transduction; Tumor Cells, Cultured; Zoledronic Acid