Oncotarget

Research Papers:

PI3K inhibitor enhances the cytotoxic response to etoposide and cisplatin in a newly established neuroendocrine cervical carcinoma cell line

Zih-Yin Lai, Hsin-Yueh Yeo, Ya-Tse Chen, Kuo-Ming Chang, Tze-Chien Chen, Yung-Jen Chuang and Shing-Jyh Chang _

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Oncotarget. 2017; 8:45323-45334. https://doi.org/10.18632/oncotarget.17335

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Abstract

Zih-Yin Lai1, Hsin-Yueh Yeo1, Ya-Tse Chen1, Kuo-Ming Chang2, Tze-Chien Chen3, Yung-Jen Chuang1 and Shing-Jyh Chang4

1Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan (R.O.C.)

2Department of Pathology, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan (R.O.C.)

3Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei 10449, Taiwan (R.O.C.)

4Department of Obstetrics and Gynecology, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan (R.O.C.)

Correspondence to:

Yung-Jen Chuang, email: [email protected]

Shing-Jyh Chang, email: [email protected]

Keywords: neuroendocrine cervical carcinoma, combination therapy, genotoxic drug, PI3K inhibitor, BEZ235

Received: February 14, 2017     Accepted: April 12, 2017     Published: April 21, 2017

ABSTRACT

Background: Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC.

Results: The stable HM-1 cell line displayed high expression levels of the neuroendocrine marker, synaptophysin. HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin synergistically inhibited HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Taken together, the data implied the combination of etoposide and cisplatin with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis.

Materials and Methods: A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 were analyzed to establish its characteristic profile. Next, HM-1 was treated with PI3K inhibitors, BKM120 and/or BEZ235, in combination with two well-known genotoxic drugs, etoposide and/or cisplatin, to evaluate which combination could serve as a more effective treatment approach. Their inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression.

Conclusions: The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a potential new treatment strategy against NECC.


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