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Reversing platinum resistance in ovarian cancer multicellular spheroids by targeting Bcl-2

Authors Yang Y, Li S, Sun Y, Zhang D, Zhao Z, Liu L

Received 24 September 2018

Accepted for publication 1 January 2019

Published 29 January 2019 Volume 2019:12 Pages 897—906

DOI https://doi.org/10.2147/OTT.S187015

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Takuya Aoki


Ya’nan Yang,1–3,* Song Li,1,* Yiting Sun,1 Di Zhang,1 Zeyi Zhao,1 Lian Liu1

1Department of Chemotherapy, Cancer Center, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; 2Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

*These authors contributed equally to this work

Purpose: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS model of ovarian cancer cells in vitro and found that the MCS cells acquired drug resistance to cisplatin. In the present study, we aimed to uncover the underlying mechanism of the platinum resistance of MCS and the potential targets to reverse the drug resistance.
Materials and methods: MCS models were established for the phenotypic studies, including proliferation, invasion, migration, drug resistance, apoptosis assays, and signaling pathway analysis. The key molecule, Bcl-2, was screened by profile analysis and validated by Western blotting. siRNA was used to verify the anti-cisplatin-induced apoptosis effect of Bcl-2. The Bcl-2 inhibitor, ABT-737, was used for improving the sensitivity of MCS to cisplatin. The 50% inhibitory concentrations (IC50) were measured by viability assays treated with different concentrations of cisplatin. Flow cytometry and Western blotting were used for quantification of drug-induced apoptosis.
Results: The ovarian cancer MCS showed a proliferation-stagnant but invasive phenotype when resuspended. When treated with cisplatin, MCS cells showed much higher viability, with significantly fewer apoptotic cells than the adherent cells. Levels of Bcl-2 were upregulated in ovarian cancer ascitic cells and MCS cells. Bcl-2 knockdown by siRNA or blockage by ABT-737 enhanced the cisplatin-induced apoptosis and reduced the 50% inhibitory concentrations of cisplatin for MCS by 58.5% and 88.2%, respectively.
Conclusion: The upregulated Bcl-2 contributes to cisplatin resistance in our MCS model and targeting it sensitizes the MCS to cisplatin treatment. This provides us a preliminary treatment method for ovarian cancer peritoneal metastasis.

Keywords: Bcl-2, drug resistance, molecular targeted therapy, multicellular spheroids, ovarian neoplasms
 

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