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Targeting of AKT-Signaling Pathway Potentiates the Anti-cancer Efficacy of Doxorubicin in A673 Ewing Sarcoma Cell Line

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Abstract

The phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway plays an important role in the regulation of signal transduction and broad spectrum of biological processes such as cell metabolism, proliferation, apoptosis, autophagy, senescence, and angiogenesis. Given that activation of (PI3K)/Akt/mTOR signaling is documented for a broad spectrum of human malignancies supporting their growth and progression, the components of this pathway are considered prospective molecular targets for anti-cancer therapies. Here, we report the activation of Akt signaling in A673 Ewing’s sarcoma cell line when compared to non-transformed BJ tert fibroblasts. MK2206, a well-known Akt inhibitor, synergistically increases doxorubicin(Dox)-induced cytotoxicity in A673 cells. In particular, inhibition of Akt signaling in A673 tumor cells potentiated Dox-induced apoptosis and inhibited proliferation of tumor cells. Inhibition of Akt signaling in Dox-treated A673 cells was associated with decreased expression of Rad51 recombinase, thereby suggesting unsuccessful homology-mediated repair of DNA damage induced by topoisomerase II inhibitor. This was consistent with decreased levels of DNA damage repair (DDR) proteins (e.g., phosphorylated forms of ATR, BRCA1, Chk1, and Chk2) in tumor cells treated with combination of MK2206 and Dox. Of note, expression of phosphorylated form of gamma-H2AX in A673 cells treated with Dox in presence of MK2206 was increased, thereby revealing unrepaired DNA damage in Akt-inhibited cells. Collectively, pharmacological inhibition of Akt signaling synergistically increases the efficiency of doxorubicin in Ewing sarcoma A673 cell line and might serve as a prospective molecular target in ES to enhance cytotoxic effects of DNA-topoisomerase II inhibitors.

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Funding

This work is funded by the International Scientific Board for Young Scientists of Kazan State Medical University (KSMU) (Recipient: Aigul Galembikova).

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  1. Department of Pathology, Kazan State Medical University, Kazan, Russia

    A. Galembikova & S. Boichuk

  2. Central Research Laboratory, Kazan State Medical University, Kazan, Russia

    S. Boichuk

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Galembikova, A., Boichuk, S. Targeting of AKT-Signaling Pathway Potentiates the Anti-cancer Efficacy of Doxorubicin in A673 Ewing Sarcoma Cell Line. BioNanoSci. 11, 1070–1082 (2021). https://doi.org/10.1007/s12668-021-00901-x

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