Browsing by Author "Owen, G. I."

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    Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase
    (WILEY, 2010) Kato, S.; Smalley, S.; Sadarangani, A.; Chen Lin, K.; Oliva, B.; Branes, J.; Carvajal, J.; Gejman, R.; Owen, G. I.; Cuello, M.
    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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    MATERNAL OBESITY IMPAIRS MIGRATION OF FETAL ENDOTHELIUM INVOLVING ENDOPLASMIC RETICULUM STRESS
    (W B SAUNDERS CO LTD, 2015) Villalobos Labra, R.; Saez, P. J.; Gonzalez, I.; Westermeier, F.; Sobrevia, L.; Casanello, P.; Owen, G. I.; Farias Jofre, M.
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    Simvastatin interferes with cancer 'stem-cell' plasticity reducing metastasis in ovarian cancer
    (2018) Kato, S.; Liberona, M. F.; Cerda-Infante, J.; Sanchez, M.; Henriquez, J.; Bizama, C.; Bravo, M. L.; Gonzalez, P.; Gejman, R.; Branes, J.; Garcia, K.; Ibanez, C.; Owen, G. I.; Roa, J. C.; Montecinos, V.; Cuello, M. A.
    Cell plasticity of 'stem-like' cancer-initiating cells (CICs) is a hallmark of cancer, allowing metastasis and cancer progression. Here, we studied whether simvastatin, a lipophilic statin, could impair the metastatic potential of CICs in high-grade serous ovarian cancer (HGS-ovC), the most lethal among the gynecologic malignancies. qPCR, immunoblotting and immunohistochemistry were used to assess simvastatin effects on proteins involved in stemness and epithelial-mesenchymal cell plasticity (EMT). Its effects on tumor growth and metastasis were evaluated using different models (e.g., spheroid formation and migration assays, matrigel invasion assays, 3D-mesomimetic models and cancer xenografts). We explored also the clinical benefit of statins by comparing survival outcomes among statin users vs non-users. Herein, we demonstrated that simvastatin modifies the stemness and EMT marker expression patterns (both in mRNA and protein levels) and severely impairs the spheroid assembly of CICs. Consequently, CICs become less metastatic in 3D-mesomimetic models and show fewer ascites/tumor burden in HGS-ovC xenografts. The principal mechanism behind statin-mediated effects involves the inactivation of the Hippo/YAP/RhoA pathway in a mevalonate synthesis-dependent manner. From a clinical perspective, statin users seem to experience better survival and quality of life when compared with non-users. Considering the high cost and the low response rates obtained with many of the current therapies, the use of orally or intraperitoneally administered simvastatin offers a cost/effective and safe alternative to treat and potentially prevent recurrent HGS-ovCs.
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    The identification of two subgroups of obese women with differing endometrial proliferation levels: potential consequences in the development of endometrial cancer
    (2012) Villavicencio, A.; Aguilar, G.; Acuna, J.; Gabler, F.; Soto, E.; Gaete, F.; Penaloza, P.; Celis, M.; Owen, G. I.
    Enhanced endometrial proliferation correlates obesity to type-I (estrogen-dependent) endometrial cancer (EC). Our aim was to distinguish obese women (without EC) with differing endometrial proliferation. Endometrial and blood samples were obtained from normal-weight and obese women without EC. Type-I EC samples were obtained from obese patients. On measuring endometrial proliferation (Ki67 and phosphorylated histone H3 (p-H3)), two groups of obese women without EC were identified: obese(High Proliferating) (O-HP) and obese(Low Proliferating) (O-LP). Increased Ki67 (88.5%, P<0.001), p-H3 (62.6%, P<0.01), 17 beta-estradiol/progesterone ratio (46.3%, P<0.01) and endometrial estrogen receptor alpha (ER alpha) (82.2%, P<0.001) were observed in O-HP compared with O-LP patients. ECs possessed similar ER alpha and enhanced proliferation as O-HP, suggesting that O-HP women are at higher risk of type-I EC. O-LP women were indistinguishable from normal-weight women regarding these determinants of endometrial proliferation, ER alpha and 17 beta-estradiol/progesterone ratio. Our data may further define the obesity phenotype in regards to type-I EC risk and may help identify obese women more susceptible to develop type-I EC, allowing early intervention and a potential reduction in mortality.