The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer

<p>Abstract</p> <p>Background</p> <p>Advanced endometrial cancer often shows resistance to clinical chemotherapy although potencies of anticancer drugs <it>in vitro </it>are promising. The disparity suggests that <it>in vi</it>vo microenvironment...

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Main Authors: Chitcholtan Kenny, Sykes Peter H, Evans John J
Format: Article
Language:English
Published: BMC 2012-03-01
Series:Journal of Translational Medicine
Online Access:http://www.translational-medicine.com/content/10/1/38
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author Chitcholtan Kenny
Sykes Peter H
Evans John J
author_facet Chitcholtan Kenny
Sykes Peter H
Evans John J
author_sort Chitcholtan Kenny
collection DOAJ
description <p>Abstract</p> <p>Background</p> <p>Advanced endometrial cancer often shows resistance to clinical chemotherapy although potencies of anticancer drugs <it>in vitro </it>are promising. The disparity suggests that <it>in vi</it>vo microenvironments are not recapitulated by <it>in vitro </it>models used for preclinical testing. However, spheroids replicate some important properties of tumours <it>in vivo</it>. Therefore, for the first time, we compared effects of doxorubicin and cisplatin on 3D multicellular structures and 2D cell monolayers of endometrial cancer cells.</p> <p>Methods</p> <p>3D multicellular structures were generated by culturing cancer cells on non-adherent surfaces; and for comparison cell monolayers were cultured on adherent culture plates. Ishikawa, RL95-2, and KLE cell lines were studied. Morphologies of 3D multicellular structures were examined. After 48 hours treatment with anticancer drugs, apoptosis, proliferation, glucose metabolism and vascular endothelial growth factor (VEGF) were analysed. Immunostaining of PCNA, Glut-1, p-Erk1/2, SOD-1 and p-Akt1/2/3 was also performed.</p> <p>Results</p> <p>Distinct 3D multicellular morphologies were formed by three different endometrial cancer cell lines. Doxorubicin induced less apoptosis in 3D multicellular structures of high grade cancer cells (RL95-2 and KLE cell lines) than in cell monolayers. Parallel alterations in Erk1/2 phosphorylation and cell proliferation might suggest they were linked and again doxorubicin had less effect on 3D multicellular structures than cell monolayers. On the other hand, there was no correlation between altered glucose metabolism and proliferation. The responses depended on cancer cell lines and were apparently not mediated by altered Glut-1 levels. The level of SOD-1 was high in 3D cell cultures. The effects on VEGF secretion were various and cancer cell line dependent. Importantly, both doxorubicin and cisplatin had selective paradoxical stimulatory effects on VEGF secretion. The microenvironment within 3D multicellular structures sustained Akt phosphorylation, consistent with it having a role in anchorage-independent pathways.</p> <p>Conclusions</p> <p>The cancer cells responded to microenvironments in a distinctive manner. 3D multicellular structures exhibited greater resistance to the agents than 2D monolayers, and the differences between the culture formats were dependent on cancer cell lines. The effects of anticancer drugs on the intracellular mediators were not similar in 3D and 2D cultures. Therefore, using 3D cell models may have a significant impact on conclusions derived from screening drugs for endometrial carcinomas.</p>
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spelling doaj.art-8d81c33e9b6944e382394e8df1deccd72022-12-22T00:08:47ZengBMCJournal of Translational Medicine1479-58762012-03-011013810.1186/1479-5876-10-38The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancerChitcholtan KennySykes Peter HEvans John J<p>Abstract</p> <p>Background</p> <p>Advanced endometrial cancer often shows resistance to clinical chemotherapy although potencies of anticancer drugs <it>in vitro </it>are promising. The disparity suggests that <it>in vi</it>vo microenvironments are not recapitulated by <it>in vitro </it>models used for preclinical testing. However, spheroids replicate some important properties of tumours <it>in vivo</it>. Therefore, for the first time, we compared effects of doxorubicin and cisplatin on 3D multicellular structures and 2D cell monolayers of endometrial cancer cells.</p> <p>Methods</p> <p>3D multicellular structures were generated by culturing cancer cells on non-adherent surfaces; and for comparison cell monolayers were cultured on adherent culture plates. Ishikawa, RL95-2, and KLE cell lines were studied. Morphologies of 3D multicellular structures were examined. After 48 hours treatment with anticancer drugs, apoptosis, proliferation, glucose metabolism and vascular endothelial growth factor (VEGF) were analysed. Immunostaining of PCNA, Glut-1, p-Erk1/2, SOD-1 and p-Akt1/2/3 was also performed.</p> <p>Results</p> <p>Distinct 3D multicellular morphologies were formed by three different endometrial cancer cell lines. Doxorubicin induced less apoptosis in 3D multicellular structures of high grade cancer cells (RL95-2 and KLE cell lines) than in cell monolayers. Parallel alterations in Erk1/2 phosphorylation and cell proliferation might suggest they were linked and again doxorubicin had less effect on 3D multicellular structures than cell monolayers. On the other hand, there was no correlation between altered glucose metabolism and proliferation. The responses depended on cancer cell lines and were apparently not mediated by altered Glut-1 levels. The level of SOD-1 was high in 3D cell cultures. The effects on VEGF secretion were various and cancer cell line dependent. Importantly, both doxorubicin and cisplatin had selective paradoxical stimulatory effects on VEGF secretion. The microenvironment within 3D multicellular structures sustained Akt phosphorylation, consistent with it having a role in anchorage-independent pathways.</p> <p>Conclusions</p> <p>The cancer cells responded to microenvironments in a distinctive manner. 3D multicellular structures exhibited greater resistance to the agents than 2D monolayers, and the differences between the culture formats were dependent on cancer cell lines. The effects of anticancer drugs on the intracellular mediators were not similar in 3D and 2D cultures. Therefore, using 3D cell models may have a significant impact on conclusions derived from screening drugs for endometrial carcinomas.</p>http://www.translational-medicine.com/content/10/1/38
spellingShingle Chitcholtan Kenny
Sykes Peter H
Evans John J
The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
Journal of Translational Medicine
title The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
title_full The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
title_fullStr The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
title_full_unstemmed The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
title_short The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
title_sort resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3d and 2d endometrial cancer
url http://www.translational-medicine.com/content/10/1/38
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