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Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase.

Kato S, Smalley S, Sadarangani A, Chen-Lin K, Oliva B, Brañes J, Carvajal J, Gejman R, Owen GI, Cuello M - J. Cell. Mol. Med. (2009)

Bottom Line: Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures.The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect.In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

ABSTRACT
Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

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(A) Comparative effects in cell survival between treatment with lipophilic statins (lovastatin: lov; simvastatin: sim; used at 10 uM) and chemotherapies (doxorubicin: dox; cisplatin: cis Pt; and paclitaxel: pacl; all used at 5 uM) in three cancerous primary tissue cultures and an immortalized ovarian cell line (HOSE). (B) Effects in cell viability by the combination of statins (lovastatin: lov, and simvastatin: sim, at 1 uM) and different chemotherapies (at 5 uM) in A2780 cells. (C) Similar experiment in a primary tissue culture from recurrent uterine cancer but using lower concentrations of chemotherapies (at 1 uM). Cell viability was measured by MTS assays upon 48 hrs of treatment.
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fig10: (A) Comparative effects in cell survival between treatment with lipophilic statins (lovastatin: lov; simvastatin: sim; used at 10 uM) and chemotherapies (doxorubicin: dox; cisplatin: cis Pt; and paclitaxel: pacl; all used at 5 uM) in three cancerous primary tissue cultures and an immortalized ovarian cell line (HOSE). (B) Effects in cell viability by the combination of statins (lovastatin: lov, and simvastatin: sim, at 1 uM) and different chemotherapies (at 5 uM) in A2780 cells. (C) Similar experiment in a primary tissue culture from recurrent uterine cancer but using lower concentrations of chemotherapies (at 1 uM). Cell viability was measured by MTS assays upon 48 hrs of treatment.

Mentions: A recent retrospective study in patients with ovarian cancer, which were treated with surgery plus chemotherapy, demonstrated that patients using statins during their treatment experienced better survival than those non-users [24]. This prompted us to investigate the effects of statins used in combination with chemotherapy in gynaecological cancers. We also wanted to compare the effect of statins used alone with current chemotherapies, both in the capacity to kill tumour cells as in the collateral effects on normal tissues. We analysed the effect of lovastatin and simvastatin in the absence or presence of the chemotherapeutic reagents doxorubicin, cisplatin and paclitaxel, in the immortalized non-cancerous cell line HOSE, in A2780 ovarian cancer cells and in three primary tissue cultures, two established from advanced ovarian cancer (from primary tumour and ascites) and the other from a recurrent uterine cancer. As shown in Figure 10A, chemotherapy drastically reduces the cell viability of cells of both normal and cancerous ovarian origin. In contrast, lovastatin and simvastatin demonstrate minimal effects on normal tissue but reduced by 50% cell viability of primary tissue cultures from ovarian cancer. Statins in combination with the different chemotherapeutic reagents, at similar concentrations, resulted in an additive effect on cell viability in both A2780 cells (Fig. 10B) and cancerous primary tissue cultures (data not shown). However, a synergistic effect is observed if same concentrations of statins are combined with lower concentrations of chemotherapies (Fig. 10C). This synergism was confirmed by dose-effect analysis (data not shown). More importantly, when ovarian cancer cells were treated with statins in combination with chemotherapies to which they were resistant an augmentation in cell death effect was observed over a wide range of concentrations (using statins from 0.25 uM to 2.5 uM in a ratio 1:5 with the chemotherapeutic drug).


Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase.

Kato S, Smalley S, Sadarangani A, Chen-Lin K, Oliva B, Brañes J, Carvajal J, Gejman R, Owen GI, Cuello M - J. Cell. Mol. Med. (2009)

(A) Comparative effects in cell survival between treatment with lipophilic statins (lovastatin: lov; simvastatin: sim; used at 10 uM) and chemotherapies (doxorubicin: dox; cisplatin: cis Pt; and paclitaxel: pacl; all used at 5 uM) in three cancerous primary tissue cultures and an immortalized ovarian cell line (HOSE). (B) Effects in cell viability by the combination of statins (lovastatin: lov, and simvastatin: sim, at 1 uM) and different chemotherapies (at 5 uM) in A2780 cells. (C) Similar experiment in a primary tissue culture from recurrent uterine cancer but using lower concentrations of chemotherapies (at 1 uM). Cell viability was measured by MTS assays upon 48 hrs of treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822754&req=5

fig10: (A) Comparative effects in cell survival between treatment with lipophilic statins (lovastatin: lov; simvastatin: sim; used at 10 uM) and chemotherapies (doxorubicin: dox; cisplatin: cis Pt; and paclitaxel: pacl; all used at 5 uM) in three cancerous primary tissue cultures and an immortalized ovarian cell line (HOSE). (B) Effects in cell viability by the combination of statins (lovastatin: lov, and simvastatin: sim, at 1 uM) and different chemotherapies (at 5 uM) in A2780 cells. (C) Similar experiment in a primary tissue culture from recurrent uterine cancer but using lower concentrations of chemotherapies (at 1 uM). Cell viability was measured by MTS assays upon 48 hrs of treatment.
Mentions: A recent retrospective study in patients with ovarian cancer, which were treated with surgery plus chemotherapy, demonstrated that patients using statins during their treatment experienced better survival than those non-users [24]. This prompted us to investigate the effects of statins used in combination with chemotherapy in gynaecological cancers. We also wanted to compare the effect of statins used alone with current chemotherapies, both in the capacity to kill tumour cells as in the collateral effects on normal tissues. We analysed the effect of lovastatin and simvastatin in the absence or presence of the chemotherapeutic reagents doxorubicin, cisplatin and paclitaxel, in the immortalized non-cancerous cell line HOSE, in A2780 ovarian cancer cells and in three primary tissue cultures, two established from advanced ovarian cancer (from primary tumour and ascites) and the other from a recurrent uterine cancer. As shown in Figure 10A, chemotherapy drastically reduces the cell viability of cells of both normal and cancerous ovarian origin. In contrast, lovastatin and simvastatin demonstrate minimal effects on normal tissue but reduced by 50% cell viability of primary tissue cultures from ovarian cancer. Statins in combination with the different chemotherapeutic reagents, at similar concentrations, resulted in an additive effect on cell viability in both A2780 cells (Fig. 10B) and cancerous primary tissue cultures (data not shown). However, a synergistic effect is observed if same concentrations of statins are combined with lower concentrations of chemotherapies (Fig. 10C). This synergism was confirmed by dose-effect analysis (data not shown). More importantly, when ovarian cancer cells were treated with statins in combination with chemotherapies to which they were resistant an augmentation in cell death effect was observed over a wide range of concentrations (using statins from 0.25 uM to 2.5 uM in a ratio 1:5 with the chemotherapeutic drug).

Bottom Line: Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures.The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect.In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

ABSTRACT
Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

Show MeSH
Related in: MedlinePlus