Ovarian Cancer Tumorigenesis Research Articles

Dual mTOR inhibition demonstrates antiproliferative and chemosensitizing effects in chemoresistant high-grade papillary serous ovarian cancer

Objectives: To establish the effect of small molecule mTOR inhibitors on the tumorigenesis of high-grade papillary serous ovarian cancer (OVCA). To compare the effect of mTOR complex 1 inhibition (mTORiC1) vs. dual mTOR complex 1 and 2 inhibition (mTORCi1+2) with and without Carboplatin (CPP) in an in vitro model of OVCA.

Defective expression of Protein 4.1N is correlated to tumor progression, aggressive behaviors and chemotherapy resistance in epithelial ovarian cancer

ObjectiveProtein 4.1N (4.1N) is a member of the Protein 4.1 family that is involved in cellular processes such as cell adhesion, migration and signaling. In this study, we evaluated the expression of 4.1N protein and its potential roles in epithelial ovarian cancer (EOC) tumorigenesis and progression. Methods4.1N protein expression was investigated in a total of 280 samples including 74 normal tissues, 35 benign, 30 borderline and 141 malignant epithelial ovarian tumors by immunohistochemistry. Correlation between 4.1N expression levels and clinicopathologic features was statistically analyzed. The expression of 4.1N in EOC cell lines was examined by western blotting. ResultsImmunohistochemistry analysis revealed that, although there was no loss of 4.1N expression in normal tissues and benign tumors, absence of Protein 4.1N was significantly more common in EOCs (44.0%) than in borderline tumors (3.3%) (p<0.001). Furthermore, loss or decreased expression of 4.1N protein expression was correlated with malignant potential of the tumors (14.3% in benign tumors, 56.7% in borderline tumors and 92.9% in malignancy) (p<0.001). In EOC samples, loss of 4.1N protein was significantly associated with advanced-stage (p=0.004), ascites (p=0.009), omental metastasis (p=0.018), suboptimal debulking (p=0.024), poorly histological differentiation (p=0.009), high-grade serous carcinoma (p=0.001), short progression-free-survival (p=0.018) and poor chemosensitivity to first-line chemotherapy (p=0.029). Moreover, western blotting analysis revealed that expression of 4.1N protein was lost in 4/8 (50%) EOC cell lines. Conclusions4.1N protein expression level was significantly decreased during malignant transformation of epithelial ovarian tumors and that loss of 4.1N expression was closely correlated to poorly differentiated and biologically aggressive EOCs.

Inhibitory effects of STAT3 decoy oligodeoxynucleotides on human epithelial ovarian cancer cell growth in vivo

The signal transducer and activator of transcription 3 (STAT3) regulates target gene expression by binding to a consensus DNA sequence within the promoter of the target genes. The constitutive activation of STAT3 has been shown to contribute to tumorigenesis in ovarian cancer and it has been reported to be a key factor for drug resistance in ovarian cancer. STAT3-specific decoy oligodeoxynucleotides (ODNs) (STAT3 decoy ODNs) that contain a consensus DNA sequence inhibit the transcriptional activity of STAT3, leading to cancer cell death. However, their mechanisms of action are unclear and little information is available as to the effects and the toxicity of STAT3 decoy ODNs in vivo. In this study, we established subcutaneous xenografts of SKOV3 human ovarian cancer cells in nude mice, evaluated the antitumor effects of STAT3 decoy ODNs on xenografted nude mice, and investigated the mechanisms behind the antitumor effects of STAT3 decoy ODNs targeting the STAT3 signaling pathway in vivo. The results revealed that the STAT3 decoy ODN inhibited ovarian cancer cell growth and promoted ovarian cancer cell apoptosis in vivo. Western blot analysis indicated that the STAT3 decoy ODN downregulated the protein expression levels of matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2, and upregulated the protein expression levels of caspase-3 in vivo. H&E staining was used to detect the side-effects of the STAT3 decoy ODN in the vital organs of the nude mice. We found that there were no significant abnormalities in the vital organs of the nude mice apart from slight inflammation and necrosis in parts of the hepatic lobule. The data from the present study suggest that decoy ODNs targeting STAT3 may be an effective therapeutic approach for the treatment of ovarian cancer in vivo.

Alterations in Expression Pattern of Splicing Factors in Epithelial Ovarian Cancer and its Clinical Impact

Alternative splicing represents an important nuclear mechanism in the posttranscriptional regulation of gene expression, which is frequently altered during tumorigenesis. Previously, we described marked changes in alternative splicing of the CD44 gene in ovarian and breast cancer as well as specific induction of distinct splicing factors during tumor development. The present study was focused on the expression profiles of different splicing factors, including classical serine-arginine (SR) proteins including ASF/SF2, hTra2β1, hTra2α, and Y-box-binding protein (YB-1) in physiological and malignant epithelial ovarian tissue to evaluate their expression pattern with regard to tumor development and disease progression. Expression levels of the different splicing factors were analyzed in physiological epithelial ovarian tissue samples, primary tumors, and metastatic samples of patients with a diagnosis of epithelial ovarian cancer using quantified reverse transcription polymerase chain reaction analysis. We examined more closely the splicing factor hTra2β1 using Western blot analysis and immunohistochemistry. The analysis revealed a marked and specific induction of ASF/SF2, SRp20, hTra2β1, and YB-1 in primary tumors as well as in their metastatic sites. However, in our patient cohort, no induction was seen for the other investigated splicing factors SRp55, SRp40, and hTra2α. Our results suggest a specific induction of distinct splicing factors in ovarian cancer tumorigenesis. The involvement of hTra2β1, YB-1, SRp20, and ASF/SF2 in exon recognition and alternative splicing may be important for gene regulation of alternatively spliced genes like CD44 with potential functional consequences in this tumor type leading to progression and metastasis.

RETRACTED: The Role of microRNAs in the Tumorigenesis of Ovarian Cancer

Epithelial ovarian cancer (EOC) is a complex disease, with multiple histological subtypes recognized. There have been major advances in the understanding of the cellular and molecular biology of this human malignancy, however the survival rate of women with EOC has changed little since platinum-based-treatment was introduced more than 30 years ago. Since 2006, an increasing number of studies have indicated an essential role for microRNAs (miRNAs) in ovarian-cancer tumorigenesis. Several miRNA profiling studies have shown that they associate with different aspects of ovarian cancer (tumor subtype, stage, histological grade, prognosis, and therapy resistance) and pointed to a critical role for miRNAs in the pathogenesis and progression of EOC. In this review, we discuss the current data concerning the accumulating evidence of the modulated expression of miRNAs in EOC, their role in diagnosis, prognosis, and prediction of response to therapy. Given the heterogeneity of this disease, it is likely that increases in long-term survival might be also achieved by translating the recent insights of miRNAs involvement in EOC into novel targeted therapies that will have a major impact on the management of ovarian cancer.

Dual mTOR inhibition demonstrates antiproliferative and chemosensitizing effects in chemoresistant high-grade papillary serous ovarian cancer

Objective: To establish the effect of small-molecule mTOR inhibitors on the tumorigenesis of high-grade papillary serous ovarian cancer (OVCA) and to compare the effect of mTOR complex 1 inhibition (mTORiC1) vs. dual mTOR complex 1 and 2 inhibition (mTORCi1+2) with and without carboplatin (CPP) in an in vitro model of OVCA.

The oncogenic role of human epididymis protein (HE4): Promotion of tumorigenesis, cell survival, and cisplatin resistance in ovarian cancer in an in vivo mouse model

The oncogenic role of human epididymis protein (HE4): Promotion of tumorigenesis, cell survival, and cisplatin resistance in ovarian cancer in an in vivo mouse model

Phase II clinical trial of six mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumors.

TPS5615 Background: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumor cells with these mutations demonstrate increased sensitivity to cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor, AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin (Issaeva 2010). Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. This multi-center phase II single arm trial was set up to investigate the activity and safety of 6MP with methotrexate in patients with breast or ovarian cancer who are known to have a BRCA mutation. Methods: Two-stage Simon compromise design (Jung 2001, Jung 2004) with α=0.20, power=90% to detect an increase in activity from 10 to 20%. 1st stage: if ≤ 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility; 2nd stage: if ≥9/65 evaluable patients respond at 8 weeks the treatment will be regarded as potentially effective and a phase III trial will be considered if the treatment appears safe and well-tolerated. 65 patients with BRCA defective cancer progressing after at least one prior chemotherapy or relapsed platinum resistant ovarian cancer, ECOG performance status 0-2 will be recruited and treated with daily 6MP (75mg/m2 ) and weekly methotrexate (20mg/m2) until progression. The starting dose was later reduced by 25% due to excess of expected toxicity. Patients with low TPMT activity or a low/low genotype are excluded due to the risk of increased toxicity. Prior treatment with a PARP inhibitor is permissible. Primary outcome: objective response at 8 weeks: complete, partial response or stable disease defined by RECIST 1.1. Secondary outcomes include safety, PFS, OS and quality of life. Of the 46 patients screened for TMPT activity between 15 Jun2009 and 05Dec 2012 from 12 UK sites, 31 patients were recruited. The pre-specified activity goal for the 1st stage was met and accrual into the 2nd stage continues. Clinical trial information: 2009-016846-16.

MicroRNA-155 is a novel suppressor of ovarian cancer-initiating cells that targets CLDN1

Previous cDNA microarrays indicated that CLDN1 (claudin-1) is an important gene for ovarian cancer-initiating cell (OCIC) invasion and adhesion. Here, we show that the downregulation of miR-155 in OCICs correlates with CLDN1 overexpression and the suppression of OCIC invasion. Luciferase assays indicate that miR-155 targets CLDN1 mRNA on the 3′ UTR. CLDN1 mRNA and claudin-1 protein expression were significantly decreased in miR-155-OCICs. Proliferation assays and Transwell migration assays show that miR-155 significantly suppresses the proliferative and invasive capacity of OCICs. Furthermore, miR-155 suppresses the growth of OCIC xenograft tumors. Thus, overexpression of miR-155 may prevent tumorigenesis in human ovarian cancer through downregulation of CLDN1.

TAZ Mediates Lysophosphatidic Acid-Induced Migration and Proliferation of Epithelial Ovarian Cancer Cells

Background: Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated. Methods: In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells. Results and Conclusion: Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK-ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA-stimulated migration of epithelial ovarian cancer cells.

TRPC Channels and Their Splice Variants are Essential for Promoting Human Ovarian Cancer Cell Proliferation and Tumorigenesis

TRPC channels are Ca²⁺-permeable cationic channels controlling Ca²⁺ influx response to the activation of G protein-coupled receptors and protein tyrosine kinase pathways or the depletion of Ca²⁺ stores. Here we aimed to investigate whether TRPC can act as the potential therapeutic targets for ovarian cancer. The mRNAs of TRPC1, TRPC3, TRPC4 and TRPC6 were detected in human ovarian adenocarcinoma. The spliced variants of TRPC1β, TRPC3a, TRPC4β, TRPC4γ, and TRPC6 with exon 3 and 4 deletion were highly expressed in the ovarian cancer cells, and a novel spliced isoform of TRPC1 with exon 9 deletion (TRPC1(E9del)) was identified. TRPC proteins were also detected by Western blotting and immunostaining. The expression of TRPC1, TRPC3, TRPC4 and TRPC6 was significantly lower in the undifferentiated ovarian cancer cells, but all-trans retinoic acid up-regulated the gene expression of TRPCs. The expression level was correlated to the cancer differentiation grade. The non-selective TRPC channel blockers, 2-APB and SKF-96365, significantly inhibited the cell proliferation, whilst the increase of TRPC channel activity by trypsin promoted the cell proliferation. Transfection with siRNA targeting TRPC1, TRPC3, TRPC4 and TRPC6 or application of specific blocking antibodies targeting to TRPC channels inhibited the cell proliferation. On the contrary, overexpression of TRPC1, TRPC1(E9del), TRPC3, TRPC4, and TRPC6 increased the cancer cell colony growth. These results suggest that TRPCs and their spliced variants are important for human ovarian cancer development and alteration of the expression or activity of these channels could be a new strategy for anticancer therapy.

The upregulation of signal transducer and activator of transcription 5-dependent microRNA-182 and microRNA-96 promotes ovarian cancer cell proliferation by targeting forkhead box O3 upon leptin stimulation

Leptin overexpression contributes to the tumorigenesis of ovarian cancer. However, the functional mechanism and effects remain unclear. The aberrant expression of tumor-related microRNAs may play an important role in the development of cancer. In this report, we demonstrate that crosstalk between leptin and microRNA-182 and microRNA-96 affects the transformation and proliferation of ovarian cancer cells. Our results showed that leptin enhanced the colony formation of ovarian cancer cells in soft agar. A water-soluble tetrazolium salts assay revealed that leptin promoted ovarian cancer cell (SKOV3 and A2780 cells) proliferation in a time- and dose-dependent manner. The growth effects of leptin on ovarian cancer cells were mediated via the reduced expression of forkhead box O3 and its downstream targets p27 and Bim. We demonstrated that leptin upregulated miRNAs that target forkhead box O3 via luciferase reporter assay. Further examination indicated that only the inhibition of microRNA-182 and/or microRNA-96 rescued the expression of forkhead box O3 inhibited by leptin, and their mimics promoted the proliferation of ovarian cancer cells. Moreover, the signal transducer and activator of transcription 5 pathway, but not the signal transducer and activator of transcription 3 pathway, was implicated in the leptin-mediated expression of microRNA-182 and microRNA-96. In conclusion, our findings suggest that the upregulation of microRNA-182 and microRNA-96 targeting forkhead box O3 plays a significant role in the pro-proliferation effect of leptin on ovarian cancer cells, which might provide preliminary experimental clues for the development of new therapies against ovarian cancer.

TRPC Channels and Their Splice Variants are Essential for Promoting Human Ovarian Cancer Cell Proliferation and Tumorigenesis

TRPC channels are Ca2+-permeable cationic channels controlling Ca2+ influx response to the activation of G protein-coupled receptors and protein tyrosine kinase pathways or the depletion of Ca2+ stores. Here we aimed to investigate whether TRPC can act as the potential therapeutic targets for ovarian cancer. The mRNAs of TRPC1, TRPC3, TRPC4 and TRPC6 were detected in human ovarian adenocarcinoma. The spliced variants of TRPC1β, TRPC3a, TRPC4β, TRPC4γ, and TRPC6 with exon 3 and 4 deletion were highly expressed in the ovarian cancer cells, and a novel spliced isoform of TRPC1 with exon 9 deletion (TRPC1E9del) was identified. TRPC proteins were also detected by Western blotting and immunostaining. The expression of TRPC1, TRPC3, TRPC4 and TRPC6 was significantly lower in the undifferentiated ovarian cancer cells, but all-trans retinoic acid up-regulated the gene expression of TRPCs. The expression level was correlated to the cancer differentiation grade. The non-selective TRPC channel blockers, 2-APB and SKF-96365, significantly inhibited the cell proliferation, whilst the increase of TRPC channel activity by trypsin promoted the cell proliferation. Transfection with siRNA targeting TRPC1, TRPC3, TRPC4 and TRPC6 or application of specific blocking antibodies targeting to TRPC channels inhibited the cell proliferation. On the contrary, overexpression of TRPC1, TRPC1E9del, TRPC3, TRPC4, and TRPC6 increased the cancer cell colony growth. These results suggest that TRPCs and their spliced variants are important for human ovarian cancer development and alteration of the expression or activity of these channels could be a new strategy for anticancer therapy. Keywords: Calcium channels, ovarian cancer, proliferation, SKOV3 cells, TRPC

TRPC Channels and Their Splice Variants are Essential for Promoting Human Ovarian Cancer Cell Proliferation and Tumorigenesis

TRPC channels are Ca²⁺-permeable cationic channels controlling Ca²⁺ influx response to the activation of G protein-coupled receptors and protein tyrosine kinase pathways or the depletion of Ca²⁺ stores. Here we aimed to investigate whether TRPC can act as the potential therapeutic targets for ovarian cancer. The mRNAs of TRPC1, TRPC3, TRPC4 and TRPC6 were detected in human ovarian adenocarcinoma. The spliced variants of TRPC1β, TRPC3a, TRPC4β, TRPC4γ, and TRPC6 with exon 3 and 4 deletion were highly expressed in the ovarian cancer cells, and a novel spliced isoform of TRPC1 with exon 9 deletion (TRPC1(E9del)) was identified. TRPC proteins were also detected by Western blotting and immunostaining. The expression of TRPC1, TRPC3, TRPC4 and TRPC6 was significantly lower in the undifferentiated ovarian cancer cells, but all-trans retinoic acid up-regulated the gene expression of TRPCs. The expression level was correlated to the cancer differentiation grade. The non-selective TRPC channel blockers, 2-APB and SKF-96365, significantly inhibited the cell proliferation, whilst the increase of TRPC channel activity by trypsin promoted the cell proliferation. Transfection with siRNA targeting TRPC1, TRPC3, TRPC4 and TRPC6 or application of specific blocking antibodies targeting to TRPC channels inhibited the cell proliferation. On the contrary, overexpression of TRPC1, TRPC1(E9del), TRPC3, TRPC4, and TRPC6 increased the cancer cell colony growth. These results suggest that TRPCs and their spliced variants are important for human ovarian cancer development and alteration of the expression or activity of these channels could be a new strategy for anticancer therapy.

Oncolytic virotherapy for ovarian cancer.

In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology.

The Transcription Factor SPDEF Suppresses Prostate Tumor Metastasis

Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo.

Gonadotropin signalling in epithelial ovarian cancer

Ovarian cancer is the most lethal of all gynecologic malignancies, although its aetiology remains poorly understood. A role for the gonadotropins, follicle-stimulating hormone (FSH) and luteinising hormone (LH), has been implicated in a variety of different aspects of ovarian cancer tumorigenesis, including cellular proliferation, migration and invasion. This review focuses on the latest advances in knowledge concerning signalling pathways and functional consequences of gonadotropin action, including changes in protein-, miRNA- and gene expression, in epithelial ovarian cancer cells.

MicroRNA‐199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer‐initiating cells

In ovarian cancer, CD44(+) /CD117(+) stem cells, also known as cancer-initiating cells (CICs), are highly proliferative, have a low degree of differentiation, and are resistant to chemotherapeutics. Therefore, the CD44(+) /CD117(+) subpopulation is thought to be an important target for novel therapeutic strategies. In this study, we investigated the role of microRNA-199a (miR-199a) in ovarian cancer stem cells. Luciferase reporter gene assays confirmed that miR-199a targets CD44 via an miR-199a-binding site in the 3'-UTR. CD44(+) /CD117(+) ovarian CICs were enriched from human primary ovarian tumor tissues and confirmed by flow cytometric sorting. miR-199a was cloned and transfected into ovarian CICs. CD44 mRNA and protein expression was significantly decreased in miR-199a-transfected ovarian CICs as compared with miR-199a mutant-transfected and untransfected cells. Cell cycle analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide proliferation assays, the colony formation assay and the transwell migration assay indicated that miR-199a significantly affected cell cycle regulation and suppressed the proliferation and invasive capacity of ovarian CICs in vitro. miR-199a significantly increased the chemosensitivity of ovarian CICs to cisplatin, pacitaxel, and adriamycin, and reduced mRNA expression of the multidrug resistance gene ABCG2 as compared with miR-199a mutant-transfected and untransfected cells. The expression of stemness markers was also significantly reduced in miR-199a-transfected CICs as compared with miR-199a mutant-transfected and untransfected ovarian cells. Furthermore, xenograft experiments confirmed that miR-199a suppressed the growth of xenograft tumors formed by ovarian CICs in vivo. Thus, expression of endogenous mature miR-199a may prevent tumorigenesis in human ovarian cancer by regulating expression of its target gene CD44.

New players in ovarian cancer

Ovarian cancer is the leading cause of gynecologic cancer mortality worldwide. The aim of this review is to highlight the most recent studies regarding ovarian cancer pathogenesis and the new therapeutic approaches against this insidious disease. We focus on the relevance of some cell cycle genes, transcription factors, and microRNAs in the carcinogenesis of ovarian cancer as well as on a new hypothesis for therapy using histone deacetylase inhibitors. We also report recent studies regarding some mechanisms of chemoresistance, a major obstacle in the treatment of ovarian cancer. Together these studies can improve our knowledge of ovarian cancer tumorigenesis and diagnosis providing new tools to hopefully defeat this deadly disease.

Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin

Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non-toxic and efficacious pathway-related treatment that can benefit patients with ovarian cancer.