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@article{1709996,
author = {Pavlatovská, Barbora and Machálková, Markéta and Brisudová, Petra and Pruška, Adam and Štěpka, Karel and Michálek, Jan and Nečasová, Tereza and Beneš, Petr and Šmarda, Jan and Preisler, Jan and Kozubek, Michal and Navrátilová, Jarmila},
article_location = {Lausanne},
article_number = {December},
doi = {http://dx.doi.org/10.3389/fonc.2020.581365},
keywords = {perifosine; Akt kinase; tumor environment; lactic acidosis; alkalization; signal co-registration; mass spectrometry imaging; colorectal cancer},
language = {eng},
issn = {2234-943X},
journal = {Frontiers in Oncology},
title = {Lactic Acidosis Interferes With Toxicity of Perifosine to Colorectal Cancer Spheroids: Multimodal Imaging Analysis},
url = {https://doi.org/10.3389/fonc.2020.581365},
volume = {10},
year = {2020}
}
TY - JOUR
ID - 1709996
AU - Pavlatovská, Barbora - Machálková, Markéta - Brisudová, Petra - Pruška, Adam - Štěpka, Karel - Michálek, Jan - Nečasová, Tereza - Beneš, Petr - Šmarda, Jan - Preisler, Jan - Kozubek, Michal - Navrátilová, Jarmila
PY - 2020
TI - Lactic Acidosis Interferes With Toxicity of Perifosine to Colorectal Cancer Spheroids: Multimodal Imaging Analysis
JF - Frontiers in Oncology
VL - 10
IS - December
SP - 1-18
EP - 1-18
PB - Frontiers Media S.A.
SN - 2234943X
KW - perifosine
KW - Akt kinase
KW - tumor environment
KW - lactic acidosis
KW - alkalization
KW - signal co-registration
KW - mass spectrometry imaging
KW - colorectal cancer
UR - https://doi.org/10.3389/fonc.2020.581365
L2 - https://doi.org/10.3389/fonc.2020.581365
N2 - Colorectal cancer (CRC) is a disease with constantly increasing incidence and highmortality. The treatment efficacy could be curtailed by drug resistance resulting from poordrug penetration into tumor tissue and the tumor-specific microenvironment, such ashypoxia and acidosis. Furthermore, CRC tumors can be exposed to different pHdepending on the position in the intestinal tract. CRC tumors often share upregulationof the Akt signaling pathway. In this study, we investigated the role of external pH in controlof cytotoxicity of perifosine, the Akt signaling pathway inhibitor, to CRC cells using 2D and3D tumor models. In 3D settings, we employed an innovative strategy for simultaneousdetection of spatial drug distribution and biological markers of proliferation/apoptosisusing a combination of mass spectrometry imaging and immunohistochemistry. In 3Dconditions, low and heterogeneous penetration of perifosine into the inner parts of thespheroids was observed. The depth of penetration depended on the treatment durationbut not on the external pH. However, pH alteration in the tumor microenvironment affectedthe distribution of proliferation- and apoptosis-specific markers in the perifosine-treatedspheroid. Accurate co-registration of perifosine distribution and biological response in thesame spheroid section revealed dynamic changes in apoptotic and proliferative markersoccurring not only in the perifosine-exposed cells, but also in the perifosine-free regions.Cytotoxicity of perifosine to both 2D and 3D cultures decreased in an acidic environmentbelow pH 6.7. External pH affects cytotoxicity of the other Akt inhibitor, MK-2206, in asimilar way. Our innovative approach for accurate determination of drug efficiency in 3Dtumor tissue revealed that cytotoxicity of Akt inhibitors to CRC cells is strongly dependenton pH of the tumor microenvironment. Therefore, the effect of pH should be consideredduring the design and pre-clinical/clinical testing of the Akt-targeted cancer therapy.
ER -
PAVLATOVSKÁ, Barbora, Markéta MACHÁLKOVÁ, Petra BRISUDOVÁ, Adam PRUŠKA, Karel ŠTĚPKA, Jan MICHÁLEK, Tereza NEČASOVÁ, Petr BENEŠ, Jan ŠMARDA, Jan PREISLER, Michal KOZUBEK a Jarmila NAVRÁTILOVÁ. Lactic Acidosis Interferes With Toxicity of Perifosine to Colorectal Cancer Spheroids: Multimodal Imaging Analysis. \textit{Frontiers in Oncology}. Lausanne: Frontiers Media S.A., 2020, roč.~10, December, s.~1-18. ISSN~2234-943X. Dostupné z: https://dx.doi.org/10.3389/fonc.2020.581365.
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