Ascitic fluid from advanced ovarian cancer patients compromises the activity of receptor tyrosine kinase inhibitors in 3D cell clusters of ovarian cancer cells

Wafaa Hassan; Kenny Chitcholtan; Peter Sykes; Ashley Garrill

doi:10.1016/j.canlet.2018.02.013

Ascitic fluid from advanced ovarian cancer patients compromises the activity of receptor tyrosine kinase inhibitors in 3D cell clusters of ovarian cancer cells

Cancer Lett. 2018 Apr 28:420:168-181. doi: 10.1016/j.canlet.2018.02.013. Epub 2018 Feb 10.

Authors

Wafaa Hassan¹, Kenny Chitcholtan², Peter Sykes³, Ashley Garrill⁴

Affiliations

¹ School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, 8041, New Zealand. Electronic address: wafaa.hassan@pg.canterbury.ac.nz.
² Gynaecological Oncology Research Group, Department of Obstetrics and Gynaecology, University of Otago, Christchurch Women's Hospital, 2 Riccarton Avenue, Christchurch, 8011, New Zealand. Electronic address: kenny.chitcholtan@otago.ac.nz.
³ Gynaecological Oncology Research Group, Department of Obstetrics and Gynaecology, University of Otago, Christchurch Women's Hospital, 2 Riccarton Avenue, Christchurch, 8011, New Zealand. Electronic address: peter.sykes@otago.ac.nz.
⁴ School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, 8041, New Zealand. Electronic address: ashley.garrill@canterbury.ac.nz.

PMID: 29432847
DOI: 10.1016/j.canlet.2018.02.013

Abstract

Ovarian cancer patients in the advanced stages of the disease show clinical ascites, which is associated with a poor prognosis. There is limited understanding of the effect of ascitic fluid on ovarian cancer cells and their response to anticancer drugs. We investigated the antitumour effects of EGFR/Her-2 (canertinib) and c-Met (PHA665752) inhibitors in a 3D cell model of three ovarian cancer lines. Single and combined inhibitor treatments affected cell growth of OVCAR-5 and SKOV-3 cell lines but not OV-90 cell line. Growth reduction was correlated with the down expression of PCNA, EGFR, HER-2, c-MET, ERK and AKT and their phosphorylation status in cells in growth factor supplemented media. However, these effects were not re-producible in OVCAR-5 and SKOV-3 cell lines when they were exposed to ascitic fluid obtained from three ovarian cancer patients. Serum albumin and protein components in the ascitic fluids may reduce the cellular uptake of the inhibitors.

Keywords: 3D cell culture; Ascites; EGFR; HER-2; Ovarian cancer; Targeted inhibitors; c-MET.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ascitic Fluid / metabolism*
Cell Culture Techniques
Cell Proliferation
Cell Survival
Down-Regulation
Drug Resistance, Neoplasm*
ErbB Receptors / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Humans
Indoles / pharmacology*
Models, Biological
Morpholines / pharmacology*
Ovarian Neoplasms / complications*
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / metabolism
Phosphorylation
Proliferating Cell Nuclear Antigen / metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-met / metabolism
Receptor, ErbB-2 / metabolism
Sulfones / pharmacology*
Tumor Cells, Cultured

Substances

5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
Indoles
Morpholines
PCNA protein, human
Proliferating Cell Nuclear Antigen
Protein Kinase Inhibitors
Sulfones
Canertinib
EGFR protein, human
ERBB2 protein, human
ErbB Receptors
Proto-Oncogene Proteins c-met
Receptor, ErbB-2
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases