Ascitic fluid from advanced ovarian cancer patients compromises the activity of receptor tyrosine kinase inhibitors in 3D cell clusters of ovarian cancer cells. (28th April 2018)

• Record Type: Journal Article
• Authors: Hassan, Wafaa; Chitcholtan, Kenny; Sykes, Peter; Garrill, Ashley
• Is Part Of: Cancer letters. Volume 420(2018)
• Page Start: 168
• Page End: 181
• Publication Date: 2018-04-28
• Subjects: Ovarian cancer -- EGFR -- HER-2 -- c-MET -- 3D cell culture -- Targeted inhibitors -- Ascites; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.02.013
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Ascitic fluid increased growth, which was correlated with the increased expression of PCNA in SKOV-3 cell aggregates. Anti-growth activity of canertinib and PHA665752 was compromised in ascitic fluid treated cell clusters of OVCAR-5 and SKOV-3, but not OV-90 cell lines. Ascitic fluid may compromise the activity of the inhibitor possibly due to the reduction of cellular uptake or increased efflux of PHA665752. Acellular components in ascitic fluid including serum albumin may limit the cellular uptake of PHA665752. Ascitic fluid increased the expression and activation of AKT only in OVCAR-5 and SKOV-3 but not OV-90 cell lines.