Combined therapy of perifosine and ABT-737 results in higher
cytotoxic effect but also induces expression of EMT markers in
colon cancer cell lines

a 2019

Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines

PAVLATOVSKÁ, Barbora, Jarmila NAVRÁTILOVÁ, Markéta MACHÁLKOVÁ, Jan MICHÁLEK, Karel ŠTĚPKA et. al.

Basic information

Original name

Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines

Name in Czech

Kombinovaná terapie perifosinu a ABT-737 u nádorů tlustého střeva vyúsťuje ve vyšší cytotoxický efekt, ale zároveň podněcuje expresi markerů epiteliálně-mesenchymální tranzice

Authors

PAVLATOVSKÁ, Barbora, Jarmila NAVRÁTILOVÁ, Markéta MACHÁLKOVÁ, Jan MICHÁLEK, Karel ŠTĚPKA, Adam PRUŠKA, Michal KOZUBEK, Petr BENEŠ, Jan ŠMARDA and Jan PREISLER

Edition

Spetses Summer School: Molecular Mechanisms in Signal Transduction and Cancer, Greece, 2019

Other information

Type of outcome

Konferenční abstrakt

Confidentiality degree

není předmětem státního či obchodního tajemství

Abstract

V originále

Colon cancer is the most common type of gastrointestinal cancer with almost 2 million new cases in Western countries in 2018. Both genetic and epigenetic alterations are involved in tumorigenesis. One of the most common aberrations during carcinogenesis is the activating mutation of PI3K/Akt signaling pathway which also modulates tumor resistance to therapy. Therefore, PI3K/Akt pathway was suggested as promising target for anticancer therapy. Perifosine is a synthetic alkyl phospholipid which inhibits Akt recruitment to the cell membrane. Despite promising results in many types of tumors, perifosine failed during clinical studies. In this study, we tested combined therapy of perifosine with ABT-737 (BCL-2 protein family inhibitor) in conditions of specific tumor-like microenvironment, such as hypoxia and acidosis. We found a synergistic cytotoxic effect of perifosine and ABT-737 in colon cancer cells. In 3D models, ABT-737 helps perifosine penetrate deeper into the spheroid and increases its cytotoxicity. Nevertheless, we also observed increased expression of EMT markers Slug/Snail and enhanced cell migration into collagen matrix after simultaneous treatment with perifosine and ABT 737 suggesting that some cells may undergo EMT and became resistant to this combined therapy.

Links

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1286/2017, interní kód MU

Name: Vývoj metod a instrumentace pro analýzu biologicky významných látek 2018

Investor: Masaryk University, Category A

MUNI/A/1359/2018, interní kód MU

Name: Vývoj metod a instrumentace pro analýzu biologicky významných látek 2019

Investor: Masaryk University, Category A

MUNI/G/0974/2016, interní kód MU

Name: Optimalizace cílené terapie kolorektálního karcinomu ovlivňováním účinnosti penetrace a cytotoxicity regulátorů buněčných signalizací

Investor: Masaryk University, INTERDISCIPLINARY - Interdisciplinary research projects

Citovat

PAVLATOVSKÁ, Barbora, Jarmila NAVRÁTILOVÁ, Markéta MACHÁLKOVÁ, Jan MICHÁLEK, Karel ŠTĚPKA, Adam PRUŠKA, Michal KOZUBEK, Petr BENEŠ, Jan ŠMARDA and Jan PREISLER. Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines. In Spetses Summer School: Molecular Mechanisms in Signal Transduction and Cancer, Greece. 2019.

@proceedings{1565956,
   author = {Pavlatovská, Barbora and Navrátilová, Jarmila and Machálková, Markéta and Michálek, Jan and Štěpka, Karel and Pruška, Adam and Kozubek, Michal and Beneš, Petr and Šmarda, Jan and Preisler, Jan},
   booktitle = {Spetses Summer School: Molecular Mechanisms in Signal Transduction and Cancer, Greece},
   title = {Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines},
   year = {2019}
}

TY  - CONF
ID  - 1565956
AU  - Pavlatovská, Barbora - Navrátilová, Jarmila - Machálková, Markéta - Michálek, Jan - Štěpka, Karel - Pruška, Adam - Kozubek, Michal - Beneš, Petr - Šmarda, Jan - Preisler, Jan
PY  - 2019
TI  - Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines
N2  - Colon cancer is the most common type of gastrointestinal cancer with almost 2 million new cases in Western countries in 2018. Both genetic and epigenetic alterations are involved in tumorigenesis. One of the most common aberrations during carcinogenesis is the activating mutation of PI3K/Akt signaling pathway which also modulates tumor resistance to therapy. Therefore, PI3K/Akt pathway was suggested as promising target for anticancer therapy. Perifosine is a synthetic alkyl phospholipid which inhibits Akt recruitment to the cell membrane. Despite promising results in many types of tumors, perifosine failed during clinical studies. In this study, we tested combined therapy of perifosine with ABT-737 (BCL-2 protein family inhibitor) in conditions of specific tumor-like microenvironment, such as hypoxia and acidosis. We found a synergistic cytotoxic effect of perifosine and ABT-737 in colon cancer cells. In 3D models, ABT-737 helps perifosine penetrate deeper into the spheroid and increases its cytotoxicity. Nevertheless, we also observed increased expression of EMT markers Slug/Snail and enhanced cell migration into collagen matrix after simultaneous treatment with perifosine and ABT 737 suggesting that some cells may undergo EMT and became resistant to this combined therapy.
ER  -

PAVLATOVSKÁ, Barbora, Jarmila NAVRÁTILOVÁ, Markéta MACHÁLKOVÁ, Jan MICHÁLEK, Karel ŠTĚPKA, Adam PRUŠKA, Michal KOZUBEK, Petr BENEŠ, Jan ŠMARDA and Jan PREISLER. Combined therapy of perifosine and ABT-737 results in higher cytotoxic effect but also induces expression of EMT markers in colon cancer cell lines. In \textit{Spetses Summer School: Molecular Mechanisms in Signal Transduction and Cancer, Greece}. 2019.

Detailed Information on Publication Record