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Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment.

ABSTRACT: BACKGROUND:Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors. METHODS:Expression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluorescence in a tissue microarray (TMA) analysis of 380 ovarian cancers and associations with clinicopathological features were sought. The effect of glycolysis pathway inhibitors on the growth of a panel of ovarian cancer cell lines was assessed by use of the SRB proliferation assay. Combination studies were undertaken combining these inhibitors with cytotoxic agents. RESULTS:Mean expression levels of GLUT1 and HKII were higher in high grade serous ovarian cancer (HGSOC), the most frequently occurring subtype, than in non-HGSOC. GLUT1 expression was also significantly higher in advanced stage (III/IV) ovarian cancer than early stage (I/II) disease. Growth dependency of ovarian cancer cells on glucose was demonstrated in a panel of ovarian cancer cell lines. Inhibitors of the glycolytic pathway (STF31, IOM-1190, 3PO and oxamic acid) attenuated cell proliferation in platinum-sensitive and platinum-resistant HGSOC cell line models in a concentration dependent manner. In combination with either cisplatin or paclitaxel, 3PO (a novel PFKFB3 inhibitor) enhanced the cytotoxic effect in both platinum sensitive and platinum resistant ovarian cancer cells. Furthermore, synergy was identified between STF31 (a novel GLUT1 inhibitor) or oxamic acid (an LDH inhibitor) when combined with metformin, an inhibitor of oxidative phosphorylation, resulting in marked inhibition of ovarian cancer cell growth. CONCLUSIONS:The findings of this study provide further support for targeting the glycolytic pathway in ovarian cancer and several useful combinations were identified.

SUBMITTER: Xintaropoulou C

PROVIDER: S-EPMC5987622 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment.

Xintaropoulou Chrysi C Ward Carol C Wise Alan A Queckborner Suzanna S Turnbull Arran A Michie Caroline O CO Williams Alistair R W ARW Rye Tzyvia T Gourley Charlie C Langdon Simon P SP

BMC cancer 20180605 1

<h4>Background</h4>Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors.<h4>Methods</h4>Expression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluoresc ...[more]

PMID: 29866066

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Project description:BackgroundOvarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide.Three-quarters of women present when the disease has spread through-put the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy, with or without taxanes. Although initial responses to chemotherapy are often good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy agents. Increased understanding about the molecular basis of ovarian cancer has lead to the development of novel agents, which work in different ways to conventional chemotherapy. These include DNA-repair pathway inhibitors, the commonest of which are the PARP (poly (ADP-ribose) polymerase) inhibitors. It is therefore important to compare their effectiveness and side effects of these novel agents to assess their role in the treatment of advanced ovarian cancer, especially as treatment of advanced disease is aiming to improve length of survival and quality of life (QoL).ObjectivesTo compare the effectiveness and harmful effects of interventions, which inhibit DNA-repair pathways, in the treatment of ovarian cancer.Search strategyRCTs were identified by searching The Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2009), The Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, MEDLINE (1990 to June 2009), EMBASE (1990 to June 2009), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.Selection criteriaAdult women with histologically proven ovarian cancer who were randomised to treatment groups which either compared DNA-repair pathway inhibitors with no treatment or DNA-repair pathway inhibitors together with conventional chemotherapy compared with conventional chemotherapy alone.Data collection and analysisTwo review authors independently assessed whether potentially relevant studies met the inclusion criteria. Searches for additional data and information were also performed by two independent review authors. No trials were found and therefore no data were analysed, so only information on excluded references was collected.Main resultsThe search strategy identified 473 unique references of which 461 were excluded on the basis of title and abstract. The remaining 12 articles were retrieved in full, but none satisfied the inclusion criteria. However, two ongoing randomised phase II clinical trials were identified from the clinical trials databases that met our inclusion criteria, but no preliminary data were available.Authors' conclusionsThere are to date no published RCT data on the effectiveness and side effects of DNA-repair pathways inhibitors used alone or in association with conventional chemotherapy in the treatment of ovarian cancer. On-going trials have been identified and results are awaited and will be included in future updates of this review.

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Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment.

Publications

Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment.

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