Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

Wilson, Andrew J.; Fadare, Oluwole; Beeghly–Fadiel, Alicia; Son, Deok‐Soo; Liu, Qi; Zhao, Shilin; Saskowski, Jeanette; Uddin, Md. Jashim; Daniel, Cristina; Crews, Brenda C.; Lehmann, Brian D.; Pietenpol, Jennifer A.; Crispens, Marta A.; Marnett, Lawrence J.; Khabele, Dineo

doi:10.18632/oncotarget.3860

Cited by 35 publications

(39 citation statements)

References 70 publications

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“…The interaction between fixed ratios of panobinostat and olaparib was measured with the Combination Index (CI) method [25]. Clonogenic assays were performed and quantified as described [26]. …”

Section: Methodsmentioning

confidence: 99%

Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

Wilson

Sarfo-Kantanka

Barrack

et al. 2016

Gynecologic Oncology

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Objective Homologous recombination (HR) proficient ovarian cancers, including CCNE1 (cyclin E)-amplified tumors, are resistant to poly (ADP-ribose) polymerase inhibitors (PARPi). Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Our goal was to determine whether panobinostat, a newly FDA-approved HDACi, can sensitize cyclin E, HR-proficient ovarian cancer cells to the PARPi olaparib. Methods Expression levels of CCNE1 (cyclin E), BRCA1, RAD51 and E2F1 in ovarian tumors and cell lines were extracted from The Cancer Genome Atlas (TCGA) and Broad-Novartis Cancer Cell Line Encyclopedia (CCLE). In HR-proficient ovarian cancer cell line models (OVCAR-3, OVCAR-4, SKOV-3, and UWB1.289 + BRCA1 wild-type), cell growth and viability were assessed by sulforhodamine B and xenograft assays. DNA damage and repair (pH2AX and RAD51 co-localization and DRGFP reporter activity) and apoptosis (cleaved PARP and cleaved caspase-3) were assessed by immunofluorescence and Western blot assays. Results TCGA and CCLE data revealed positive correlations (Spearman) between cyclin E E2F1, and E2F1 gene targets related to DNA repair (BRCA1 and RAD51). Panobinostat downregulated cyclin E and HR repair pathway genes, and reduced HR efficiency in cyclin E-amplified OVCAR-3 cells. Further, panobinostat synergized with olaparib in reducing cell growth and viability in HR-proficient cells. Similar co-operative effects were observed in xenografts, and on pharmacodynamic markers of HR repair, DNA damage and apoptosis. Conclusions These results provide preclinical rationale for using HDACi to reduce HR in cyclin E-overexpressing and other types of HR-proficient ovarian cancer as a means of enhancing PARPi activity.

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Section: Methodsmentioning

confidence: 99%

Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

Wilson

Sarfo-Kantanka

Barrack

et al. 2016

Gynecologic Oncology

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“…The aforementioned findings suggest that blueberry juice decreases the levels of COX-1 and COX-2, and inhibits the progression of OC. Furthermore, detecting the levels of COX-1 and COX-2 aid in the prediction of patients at risk for OC, as reported in previous studies (24,34). Blueberry juice therapy may therefore provide a non-pharmaceutical treatment for patients with OC.…”

Section: Discussionmentioning

confidence: 62%

“…Subsequent to the blueberry treatment, the volumes of OC in the 500 mg group significantly decreased by 40% compared with the group that received no Blueberry juice affects the mRNA levels of COX-1 and COX-2 of OC in the mouse model. The present study investigated the effect of blueberries on the mRNA levels of COX-1 and COX-2 of OC in a mouse model, which are biomarkers of OC (24,28). The mRNA levels of COX-1 and COX-2 of OC in the mice were the highest in the control group compared with those in the models treated with blueberry juice (P=0.006; Fig.…”

Section: Effects Of Blueberry On Tumor Volumementioning

confidence: 81%

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Blueberries inhibit cyclooxygenase-1 and cyclooxygenase-2 activity in human epithelial ovarian cancer

Lin

2017

Oncology Letters

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Abstract. Ovarian cancer (OC) is the sixth and eighth leading cause of cancer mortality among women in developed and developing countries, respectively. Medical therapy is the main method for the treatment of OC. However, drug toxicity and the marked side effects of chemotherapy limit the usage and therapeutic results of the treatments. Therefore, the identification of multi-target agents with few side effects and high effectiveness is required. Traditional Chinese medicine has been used clinically to treat various types of cancer for thousands of years and is considered to possess multiple components and agents, which exert efficient therapeutic functions with few side effects. Although blueberries have previously been used to treat various types of cancer, the effect on OC and precise molecular mechanism of function of the fruit remains unknown. Cyclooxygenase (COX)-1 and COX-2 have been reported to be the biomarkers of OC. Blueberries may affect the progression of OC by affecting COX levels. To investigate the issue, COX-1 and COX-2 were overexpressed or silenced in ovarian cancer SKOV3 cells. The effect of blueberries on SKOV3 cell viability was determined by an MTT assay. Furthermore, a mouse model for OC was established. The results indicated that blueberries inhibited the proliferation of OC cells by downregulating the levels of COX-1 and COX-2. Blueberry (400 mg daily) consumption reduced tumor size significantly in mice with OC compared with the control without blueberry treatment (P<0.05). The results suggest that blueberries should be used to develop a potential non-pharmaceutical therapy for OC.

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“…They showed that SC-560 attenuates PG production and EOC growth by reducing cell proliferation and/or accelerating apoptosis. Wilson et al20 reported that stable knockdown of COX-1 in OVCAR-3 ovarian cancer cells reduced gene expression in multiple protumorigenic pathways.Upregulation of COX-2 contributes to tumor growth and invasion in EOC. Smith et al…”

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confidence: 99%

Cyclooxygenase Inhibitors in Epithelial Ovarian Cancer Treatment

Zeng

Yi²

2018

International Journal of Gynecological Cancer

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Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer mortality among women. At present, EOC is treated with one or in a combination of treatments, commonly debulking surgery, combining a platinum-based and a taxane-based therapy; however, the patients have a risk of injury to the bowel, bladder, ureter, and vessels during surgery and many of them suffer from severe adverse effects caused by chemotherapy. Pharmaceutical inhibition of cyclooxygenase (COX) might be an important therapeutic tool in cancer treatment, as COX contributes to cancer progression by upregulating the levels of downstream metabolites. In this review article, we have discussed the role of COX in cancer progression and the therapeutic use of COX inhibitors in the treatment of EOC with subsequent clinical studies and future management. Usually, gonadotropins can promote prostaglandin E2 production in EOC cells via COX-1 and -2 upregulations through the PI3K/AKT signaling pathway. Several reports have shown that treatment of EOC cells with COX-1- and COX-2-specific inhibitors exhibits a therapeutic effect on EOC both in vitro and in vivo. However, more clinical investigations are needed to develop therapeutic COX inhibitors for the prevention and treatment of EOC without adverse effects.

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Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

Cited by 35 publications

References 70 publications

Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

Blueberries inhibit cyclooxygenase-1 and cyclooxygenase-2 activity in human epithelial ovarian cancer

Cyclooxygenase Inhibitors in Epithelial Ovarian Cancer Treatment

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