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Exploring cisplatin resistance in ovarian cancer through integrated bioinformatics approach and overcoming chemoresistance with sanguinarine.

ABSTRACT: Ovarian cancer is refractory in response towards platinum-based chemotherapy, and resistance frequently develops. We attempted to identify the driving pathways in cisplatin-resistant ovarian cancer and develop targeted therapies to overcome this resistance. Using an integrated bioinformatics approach, a GSE15372 database from NCBI's Gene Expression Omnibus database was obtained for identifying differentially expressed genes (DEGs), in which 535 DEGs were found (407 up-regulated and 128 down-regulated) in association with ovarian cancer cisplatin-resistance. Gene ontology and pathway enrichment analyses further found that aberrant activation of EGFR/ErbB2 signaling was the driving event in resistant cells. A network of dysregulated genes was built based on these identified DEGs and protein-protein interaction network, which led to the identification of 7 potential inhibitors based on screening a 77 small molecule natural product library. Sanguinarine, alone and in combination with cisplatin, was found to significantly suppress the proliferation of wt/resistant ovarian cancer cells in vitro and the growth of parental and resistant ovarian xenograft tumors in vivo. Our study suggests that EGFR/ErbB2 activation is one of the driving pathways in developing cisplatin-resistance in ovarian cancer, and that sanguinarine has the potential to be developed as an effective therapy to overcome this therapeutic resistance.

SUBMITTER: Yang L

PROVIDER: S-EPMC7137043 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exploring cisplatin resistance in ovarian cancer through integrated bioinformatics approach and overcoming chemoresistance with sanguinarine.

Yang Lihua L Zhao Hongbo H Yin Xueqin X Liang Hong H Zheng Zhi Z Shen Qiang Q Hu Wanqin W

American journal of translational research 20200315 3

Ovarian cancer is refractory in response towards platinum-based chemotherapy, and resistance frequently develops. We attempted to identify the driving pathways in cisplatin-resistant ovarian cancer and develop targeted therapies to overcome this resistance. Using an integrated bioinformatics approach, a GSE15372 database from NCBI's Gene Expression Omnibus database was obtained for identifying differentially expressed genes (DEGs), in which 535 DEGs were found (407 up-regulated and 128 down-regu ...[more]

PMID: 32269724

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Project description:Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time. Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment. Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity. Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols.

Dataset Information

Exploring cisplatin resistance in ovarian cancer through integrated bioinformatics approach and overcoming chemoresistance with sanguinarine.

Publications

Exploring cisplatin resistance in ovarian cancer through integrated bioinformatics approach and overcoming chemoresistance with sanguinarine.

Similar Datasets

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