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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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