Mauricio A Cuello

Pontifical Catholic University of Chile, CiudadSantiago, Santiago Metropolitan, Chile

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Publications (27)101.3 Total impact

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    ABSTRACT: An increase in circulating platelets, or thrombocytosis, is recognized as an independent risk factor of bad prognosis and metastasis in patients with ovarian cancer; however the complex role of platelets in tumor progression has not been fully elucidated. Platelet activation has been associated with an epithelial to mesenchymal transition (EMT), while Tissue Factor (TF) protein expression by cancer cells has been shown to correlate with hypercoagulable state and metastasis. The aim of this work was to determine the effect of platelet-cancer cell interaction on TF and "Metastasis Initiating Cell (MIC)" marker levels and migration in ovarian cancer cell lines and cancer cells isolated from the ascetic fluid of ovarian cancer patients. With informed patient consent, ascitic fluid isolated ovarian cancer cells, cell lines and ovarian cancer spheres were co-cultivated with human platelets. TF, EMT and stem cell marker levels were determined by Western blotting, flow cytometry and RT-PCR. Cancer cell migration was determined by Boyden chambers and the scratch assay. The co-culture of patient-derived ovarian cancer cells with platelets causes: 1) a phenotypic change in cancer cells, 2) chemoattraction and cancer cell migration, 3) induced MIC markers (EMT/stemness), 3) increased sphere formation and 4) increased TF protein levels and activity. We present the first evidence that platelets act as chemoattractants to cancer cells. Furthermore, platelets promote the formation of ovarian cancer spheres that express MIC markers and the metastatic protein TF. Our results suggest that platelet-cancer cell interaction plays a role in the formation of metastatic foci.
    BMC Cancer 04/2015; 15(1):290. DOI:10.1186/s12885-015-1304-z · 3.32 Impact Factor
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    ABSTRACT: Knockout models have shown that the coagulation system has a role in vascular development and angiogenesis. Herein, we report for the first time that zymogen FX and its active form (FXa) possess anti-angiogenic properties. Both the recombinant FX and FXa inhibit angiogenesis in vitro using endothelial EA.hy926 and human umbilical cord vascular endothelial cells (HUVEC). This effect is dependent on the Gla domain of FX. We demonstrate that FX and FXa use different mechanisms: the use of Rivaroxaban (RX) a specific inhibitor of FXa attenuated its anti-angiogenic properties but did not modify the anti-angiogenic effect of FX. Furthermore, only the anti-angiogenic activity of FXa is PAR-1dependent. Using in vivo models, we show that FX and FXa are anti-angiogenic in the zebrafish intersegmental vasculature (ISV) formation and in the chick embryo chorioallantoic membrane (CAM) assays. Our results provide further evidence for the non-hemostatic functions of FX and FXa and demonstrate for the first time a biological role for the zymogen FX. J. Cell. Physiol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 11/2014; 229(11). DOI:10.1002/jcp.24612 · 3.87 Impact Factor
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    ABSTRACT: To characterize the molecular mechanism and map the response element used by progesterone (P) to upregulate tissue factor (TF) in breast cancer cells. TF expression and mRNA levels were analyzed in breast cancer ZR-75 and T47D cells, using Western blot and real-time PCR, respectively. Mapping of the TF promoter was performed using luciferase vectors. Progesterone receptor (PR) and specificity protein 1 (Sp1) binding to the TF promoter were analyzed by chromatin immuno precipitation assay. Specific or selective inhibitors were used for the MEK1/2 and the c-Src pathways (UO126 and PP2, respectively). TF mRNA increase peaks at 18 h following P treatment in ZR-75 and T47D cells. P upregulation occurs via a transcriptional mechanism that depends on PR and MEK1/2 activation, PR and Sp1 transcription factors bind to a region in the TF promoter that contains three Sp1 sites. TF mRNA upregulation requires an intact PR proline-rich site (mPRO), but it is independent from c-Src. TF upregulation by P is mediated by Sp1 sites in the TF promoter region. Transcriptional upregulation in breast cancer cells occurs via a new mechanism that requires MEK1/2 activation and the mPRO site but independent of c-Src activity. PR Phosphorylation at serine 294 and 345 is not essential.
    Endocrine 05/2014; 48(1). DOI:10.1007/s12020-014-0288-9 · 3.53 Impact Factor
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    ABSTRACT: Genital prolapse affects up to 50 % of multiparous women and has an impact on quality of life (QoL) for many. Vaginal obliterative techniques are relevant in older patients who are not sexually active. We performed Labhardt's colpoperineocleisis in such patients. The objective was the evaluation of subjective outcomes of this technique using PGI-I. Retrospective cohort analysis of patients. We performed a bivariate, multivariate analysis, and survival curves for subjective improvement. Seventy-four cases were analyzed. Average age of the patients was 72 years, median parity 4, 95.9 % POP-Q stage III or IV, anterior leading edge defect in 61.1 %. Operating time: 54 min, estimated blood loss 70 ml, no intraoperative complications, 12 patients had protocol deviations with changes in the recommended type of suture. Median hospital stay was 2 days and average follow-up 24.9 months. There was 13.5 % anatomical recurrence, 3 of which (30 %) were in patients with protocol deviations. 1.9 % developed clinically significant de novo stress urinary incontinence (SUI). 64 (86 %) reported subjective improvement and 10 did not. In the subjective improvement group, 98.4 % reported being very much or much better. In the non-subjective improvement group 80 % reported that they were the same as before surgery and 20 % were worse. In bivariate analysis anatomical recurrence showed significance and persisted after multivariate analysis with an OR of 8322 for subjective failure. Labhardt's colpoperineocleisis is a safe technique with good subjective results. It has few complications, an acceptable recurrence rate, and a low rate of de novo SUI. It may be important to use the #0 or #1 polydioxanone sutures, as these are associated with better outcomes in this series. Comparative studies with other obliterative techniques are needed.
    International Urogynecology Journal 09/2013; 25(3). DOI:10.1007/s00192-013-2205-9 · 2.16 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3730-3730. DOI:10.1158/1538-7445.AM2013-3730 · 9.28 Impact Factor
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    ABSTRACT: The use of the type 2 diabetics drug metformin has been correlated with enhanced progression-free survival in ovarian cancer. The literature has speculated that this enhancement is due to the high concentration of metformin directly causing cancer cell death. However, this explanation does not fit with clinical data reporting that the women exposed to constant micromolar concentrations of metformin, as present in the treatment of diabetes, respond better to chemotherapy. Herein, our aim was to examine whether micromolar concentrations of metformin alone could bring about cancer cell death and whether micromolar metformin could increase the cytotoxic effect of commonly used chemotherapies in A2780 and SKOV3 cell lines and primary cultured cancer cells isolated from the peritoneal fluid of patients with advanced ovarian cancer. Our results in cell lines demonstrate that no significant loss of viability or change in cell cycle was observed with micromolar metformin alone; however, we observed cytotoxicity with micromolar metformin in combination with chemotherapy at concentrations where the chemotherapy alone produced no loss in viability. We demonstrate that previous exposure and maintenance of metformin in conjunction with carboplatin produces a synergistic enhancement in cytotoxicity of A2780 and SKOV3 cells (55% and 43%, respectively). Furthermore, in 5 (44%) of the 11 ovarian cancer primary cultures, micromolar metformin improved the cytotoxic response to carboplatin but not paclitaxel or doxorubicin. In conclusion, we present data that support the need for a clinical study to evaluate the adjuvant maintenance or prescription of currently approved doses of metformin during the chemotherapeutic treatment of ovarian cancer.
    Reproductive sciences (Thousand Oaks, Calif.) 05/2013; 20(12). DOI:10.1177/1933719113488441 · 2.18 Impact Factor
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    ABSTRACT: Our laboratory has implemented an in vitro assay to estimate the response to chemotherapy in ovarian cancer cells pertaining to individual patients. In two selected patients, we determined the correlation between an in vitro assay of cells from suspected ovarian cancer ascites, with the clinical chemotherapy response. Cancer cells isolated from peritoneal fluid with suspected ovarian cancer were tested for cytotoxicity with corresponding chemotherapy regimens. Circulating Cal25 levels and attending physician consultation determined clinical course and response to chemotherapy. The in vitro assay result correlated with Cal25 levels, progression free survival and attending physician evaluation. The assay predicted correctly the failure of two successive chemotherapy regimes in the first patient, while predicting a favorable clinical response in the second subject.
    Revista medica de Chile 05/2013; 141(5):669-673. · 0.37 Impact Factor
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    Revista medica de Chile 05/2013; 141(5):669-673. DOI:10.4067/S0034-98872013000500017 · 0.37 Impact Factor
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    ABSTRACT: This report is an integrated study to include the molecular simulation, physicochemical characterization and biological analysis of a paclitaxel-loaded PHBV nanoparticle that demonstrates uptake, release and cytotoxicity in cancer cell lines. Taking this nanoparticle one step closer to its use in a clinical setting, we demonstrate that it causes significant cell death in primary cultures of stage IIIc serous ovarian cancer cells isolated from six patients. Molecular simulations revealed a high affinity of paclitaxel for the water-polymer interface, thus the drug is delivered only when the polymer near it is degraded. The Fourier transform infrared spectroscopy suggests the formation of a short-lived crystalline phase, also observed in the CG simulations, and transmission electron microscopy revealed branched structures on the surface of particles, which disappeared after 4 days. Biological analyses indicated that these particles have a 48-h window of toxicity protection, allowing for the endocytosis of the particle by the cells; this finding was corroborated by confocal microscopy and flow cytometry. The low cost to synthesize PHBV using microorganisms and the potential chemical modifications of the polymer make it attractive for inexpensive, large-scale pharmaceutical production.
    Biomaterials 03/2013; DOI:10.1016/j.biomaterials.2013.02.034 · 8.31 Impact Factor
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    ABSTRACT: Brain natriuretic peptide (BNP) is synthesized by human fetal membranes, both the amnion and chorion. This locally produced BNP inhibits the contraction of the human myometrium, contributing to the maintenance of myometrial quiescence during pregnancy. We tested the hypothesis that BNP production is increased by fetal membrane stretching, which is predicted to occur in the expanding uterus, and inhibited by epidermal growth factor (EGF), whose production in the fetal membranes increases in late pregnancy. Term fetal membranes were obtained during elective cesarean delivery before labor. Sections of membranes were placed in an isolated chamber containing DMEM: F12 medium (37°C) and stretched with a 35 g weight. Medium and tissue samples were collected at 0, 3, 6, 18, and 24 hours for measurement of messenger RNA (mRNA) and BNP levels in the presence/absence of EGF (2 × 10(-9 )mol/L). Inducible nitric oxide synthase (iNOS) and β-actin were also evaluated to discard a nonspecific effect of mechanical stretch on protein expression. We found that amnion and chorion stretching increased the BNP mRNA (reverse transcription-polymerase chain reaction [RT-PCR]) and protein (radioimmunosorbent assay [RIA]) levels from 18 hours onward. The effect of stretching was inhibited by EGF (2 × 10(-9) mol/L). Stretch did not increase iNOS or β-actin protein levels. We concluded that chorion and amnion stretching may increase BNP expression in the fetal membranes during pregnancy, while increasing biological activity of EGF may decrease BNP production in the chorion and amnion late in pregnancy. We postulate BNP is an important regulator of myometrial contractility during pregnancy, and its production is modulated by both stretch and progressive increase in EGF levels during pregnancy.
    Reproductive sciences (Thousand Oaks, Calif.) 09/2012; DOI:10.1177/1933719112459219 · 2.18 Impact Factor
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    ABSTRACT: We postulate that protein kinase C α (PKCα) may contribute to the maintenance of pregnancy myometrial quiescence in humans. We studied the changes in myometrial PKCα gene products (messenger RNA [mRNA] and protein) in 4 groups of women: preterm not in labor (PT-NL), preterm in labor (PT-L), term not in labor (T-NL), and term in labor (T-L). The degree of PKCα activation was studied by comparing the levels of particulate (active) PKCα with the total PKCα protein levels and by measuring PKCα activity in the cytosolic and particulate fractions. Protein kinase Cα abundance (mRNA and protein) did not increase during myometrial quiescence (PT-NL), whereas the level of PKCα activity significantly increased during quiescence. The activity of PKCα significantly decreased in the T-NL, T-L, and PT-L groups. These findings suggest that PKCα plays a significant role in the maintenance of myometrial quiescence and that PKCα activity must decrease at the end of pregnancy allowing myometrial activation. Additionally, our data demonstrate an association between reduced PKCα activity and preterm labor, which merits further investigation.
    Reproductive sciences (Thousand Oaks, Calif.) 08/2012; 20(1). DOI:10.1177/1933719112450335 · 2.18 Impact Factor
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    ABSTRACT: Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3  h and returning to basal levels at 18  h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women.
    Journal of Endocrinology 05/2012; 214(2):165-75. DOI:10.1530/JOE-11-0310 · 3.59 Impact Factor
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    ABSTRACT: Tissue factor (TF) serving as the receptor for coagulation factor VII (FVII) initiates the extrinsic coagulation pathway. We previously demonstrated that progesterone increases TF, coagulation and invasion in breast cancer cell lines. Herein, we investigated if tissue factor pathway inhibitor (TFPI) could down-regulate progesterone-increased TF activity in these cells. Classically, TFPI redistributes TF-FVII-FX-TFPI in an inactive quaternary complex to membrane associated lipid raft regions. Herein, we demonstrate that TF increased by progesterone is localized to the heavy membrane fraction, despite progesterone-increased coagulation originating almost exclusively from lipid raft domains, where TF levels are extremely low. The progesterone increase in coagulation is not a rapid effect, but is progesterone receptor (PR) dependent and requires protein synthesis. Although a partial relocalization of TF occurs, TFPI does not require the redistribution to lipid rafts to inhibit coagulation or invasion. Inhibition by TFPI and anti-TF antibodies in lipid raft membrane fractions confirmed the dependence on TF for progesterone-mediated coagulation. Through the use of pathway inhibitors, we further demonstrate that the TF up-regulated by progesterone is not coupled to the progesterone increase in TF-mediated coagulation. However, the progesterone up-regulated TF protein may be involved in progesterone-mediated breast cancer cell invasion, which TFPI also inhibits. J. Cell. Physiol. 226: 3278–3285, 2011. © 2011 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 12/2011; 226(12):3278 - 3285. DOI:10.1002/jcp.22689 · 3.87 Impact Factor
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    ABSTRACT: 2-Methoxyestradiol (2ME) is an endogenous metabolite of 17β-estradiol with antiangiogenic and antitumor properties, although its mechanisms of action remain unclear. Progestins in hormone replacement therapy increase the risk of breast cancer. Progesterone also enhances the procoagulant activity and invasive potential of progesterone receptor (PR)-positive breast cancer cell lines, an effect largely mediated by induction of tissue factor (TF), the cellular activator of the coagulation cascade. Here we show that 2ME abrogates the induction TF expression in progesterone-treated breast cancer cells via a mechanism that does not involve the estrogen receptor. Instead, we demonstrate that by selectively antagonizing ERK1/2 signaling in breast cancer cells, 2ME limits the transactivation potential of ligand-bound PR and inhibits the expression of endogenous progesterone targets, such as TF and signal transducer and activator of transcription 5. We further demonstrate that 2ME can alter the phosphorylation status of PR. Thus, 2ME prevents progesterone-dependent increase in breast cancer cell invasiveness and procoagulant activity by uncoupling PR from the ERK1/2 signal transduction pathway.
    Hormones and Cancer 06/2010; 1(3):117-26. DOI:10.1007/s12672-010-0019-5
  • Mauricio A Cuello, Marion Nau, Stan Lipkowitz
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    ABSTRACT: Dysregulation of apoptosis plays a major role in cancer etiology. Cancer cells often contain genetic abnormalities which allow the cells to survive under conditions that normally would trigger their demise. The identification of these mutations has changed the models of cancer progression from a disease of excessive proliferation to one of unbalanced cell death and cell growth. During the last decade, fundamental knowledge delineating the molecular mechanisms of apoptosis has emerged and now can be exploited to identify novel apoptotic modulators for the treatment of cancer.
    Breast disease 10/2009; 15:71-82.
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    ABSTRACT: We aim to demonstrate that Brain Natriuretic Peptide (BNP) is synthesized and released from the fetal membranes and mediates pregnancy myometrial quiescence. Myometrium and fetal membranes (FM) were obtained from term and preterm pregnancies at the time of cesarean section, either in labor or not in labor. BNP was measured in term and preterm FM, in culture cells, and conditioned media. We found BNP (but not ANP or CNP) inhibited contractions of preterm, but not term, human myometrium. BNP (both protein and mRNA) was detected in all tissues, conditioned media and cultured cells. BNP was higher in samples from preterm women not in labor compared to those at term not in labor. BNP concentrations were significantly reduced in women in spontaneous preterm labor. We conclude that locally produced BNP may be involved in generating myometrial quiescence during pregnancy. Further, a premature decrease of BNP production may cause preterm labor.
    Reproductive sciences (Thousand Oaks, Calif.) 02/2009; 16(1):32-42. DOI:10.1177/1933719108324137 · 2.18 Impact Factor
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    ABSTRACT: The estrogen metabolite 2-methoxyestradiol has shown antitumorigenic action in some epithelial tumors. In the present work we investigate its effects in ovarian cancer used alone or in combination with other apoptotic-inducing reagents such as tumor necrosis factor-related apoptosis-inducing ligand. To assess the effect of 2-methoxyestradiol, dose response and time courses in ovarian cancer and normal cells were conducted. Apoptosis was confirmed through DNA laddering, by flow cytometry, and Western blotting of proteins involved in the apoptotic cascade. 2-Methoxyestradiol induced apoptosis in ovarian cancer cells but not in normal counterparts. 2-Methoxyestradiol activates both the intrinsic and extrinsic apoptotic pathways. 2-Methoxyestradiol-mediated apoptosis involves reactive oxygen species generation and caspase-dependent and caspase-independent mechanisms. We also demonstrate that 2-methoxyestradiol selectively induces an additive/synergistic apoptotic response in ovarian cancer cells when used in combination with tumor necrosis factor-related apoptosis-inducing ligand. 2-Methoxyestradiol, alone or in combination with tumor necrosis factor-related apoptosis-inducing ligand, should be considered as a potential treatment for ovarian cancer.
    Reproductive sciences (Thousand Oaks, Calif.) 10/2008; 15(9):878-94. DOI:10.1177/1933719108324171 · 2.18 Impact Factor
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    ABSTRACT: Despite numerous endometrial cancer cell lines, little is know about the progression and transition of primary cultured endometrial tumours. Herein, a stage I grade III endometrial adenocarcinoma was maintained in primary culture and the phenotypic and protein expression changes were observed in relation to passage number. At early passage numbers, cultured human endometrial cancer (CHEC) cells displayed classic epithelial cell morphology, growing in groups in a glandular structure and staining positive for cytokeratin. However, with increasing passage number, CHEC cells changed in morphology to display a stromal phenotype which was accompanied by a significant reduction in cytokeratin and increases in alpha-actin and vimentin expression. Simultaneous culture of stromal cells isolated from the original tumour failed to show the same morphological characteristics or protein expression patterns. We further characterised CHEC cells through a screening of cancer related proteins, among others, caveolin-1 and Tissue factor in comparison with established cancer cell lines and corresponding non-cancerous cells. This report demonstrates that endometrial adenocarcinoma cells in culture can undergo phenotypic and protein expression changes reminiscent of epithelial-mesenchymal transition. This work suggests that primary tumours and cell lines displaying stromal morphologies may have undergone epithelial-mesenchymal transition from an adenocarcinoma origin.
    Tissue and Cell 05/2008; 40(2):95-102. DOI:10.1016/j.tice.2007.09.007 · 1.05 Impact Factor
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    ABSTRACT: Cancers of the reproductive tract account for 12% of all malignancies in women. As previous studies have shown that oestrogen metabolites can cause apoptosis, we characterised the effect of oestrogen and oestrogen metabolites on non-cancerous and cancerous human endometrial cells. Herein, we demonstrate that 2-methoxyoestradiol (2ME), but not 17beta-oestradiol, induces apoptosis in cancer cell lines and primary cultured tumours of endometrial origin. In contrast, 2ME had no effect on cell viability of corresponding normal tissue. This ability of 2ME to induce apoptosis does not require oestrogen receptor activation, but is associated with increased entry into the G2/M phases of the cell cycle and the activation of both the intrinsic and the extrinsic apoptotic pathways. The selective behaviour of 2ME on cancerous as opposed to normal tissue may be due to a reduction in 17beta-hydroxysteroid dehydrogenase type II levels in cancer cells and to a differential down-regulation of superoxide dismutase. Furthermore, we demonstrate that pre-treatment with 2ME enhances the sensitivity of reproductive tract cancer cells to the apoptotic drug tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), without the loss in cell viability to normal cells incurred by currently chemotherapeutic drugs. In conclusion, 2ME, alone or in combination with TRAIL, may be an effective treatment for cancers of uterine origin with minimal toxicity to corresponding healthy female reproductive tissue.
    Endocrine Related Cancer 07/2007; 14(2):351-68. DOI:10.1677/ERC-07-0008 · 4.91 Impact Factor
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    ABSTRACT: Cancer of the reproductive tract encompasses malignancies of the uterine corpus, cervix, ovary, Fallopian tube, among others and accounts for 15% of female cancer mortalities. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis by binding to death receptors and offers a promising cancer treatment. The goal of this study was to investigate and characterize the effect of TRAIL in endometrial cancer cell lines and normal (non-cancerous) epithelial cells of endometrial origin. We also examined the effect of TRAIL in other primary cultured cancers and normal cells of the human female reproductive tract and evaluated if TRAIL mediated apoptosis correlated with death receptors and decoy receptors 1 and 2.Herein, we demonstrate that TRAIL at concentrations which kill cancerous cells, does not mediate apoptosis or alter cell viability in normal human endometrium, ovary, cervix or Fallopian tube. The partial inhibition by a caspase 9 inhibitor and the total inhibition by a caspase 8 inhibitor demonstrates the dependency on the extrinsic apoptotic pathway. The selective mortality does not correlate with the presence of death or decoy receptors. These results suggest that TRAIL may be an effective treatment for endometrial cancer and other female reproductive cancers, with minimal secondary effects on healthy tissue.
    APOPTOSIS 02/2007; 12(1):73-85. DOI:10.1007/s10495-006-0492-z · 3.61 Impact Factor

Publication Stats

431 Citations
101.30 Total Impact Points


  • 2005–2015
    • Pontifical Catholic University of Chile
      • • División Gineco-Obstetricia
      • • Facultad de Medicina
      • • Departamento de Fisiología
      • • Departamento de Endocrinología
      CiudadSantiago, Santiago Metropolitan, Chile
  • 1999–2000
    • National Cancer Institute (USA)
      • Genetics Branch
      Maryland, United States