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

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.

• Authors: Zih-Yin Lai, Hsin-Yueh Yeo, Ya-Tse Chen, Kuo-Ming Chang, Tze-Chien Chen, Yung-Jen Chuang, Shing-Jyh Chang
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 28 Pg. 45323-45334 (Jul 11 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28484083 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers
• Phosphoinositide-3 Kinase Inhibitors
• Etoposide
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers
• Carcinoma, Neuroendocrine (drug therapy, etiology, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• DNA Damage (drug effects)
• Disease Models, Animal
• Drug Synergism
• Etoposide (pharmacology)
• Female
• Humans
• Mice
• Papillomavirus Infections (complications, virology)
• Phosphoinositide-3 Kinase Inhibitors
• Uterine Cervical Neoplasms (drug therapy, etiology, metabolism, pathology)
• Xenograft Model Antitumor Assays