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Autophagy inhibitor potentiates the antitumor efficacy of apatinib in uterine sarcoma by stimulating PI3K/Akt/mTOR pathway

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Abstract

Aim

The present study aims to examine the effects of apatinib combined with autophagy inhibitor 3-Methyladenine (3-MA) on the proliferation and apoptosis of human uterine sarcoma in FU-MMT-1 and MES-SA cells and its tumor inhibition effect in xenograft model of uterine sarcoma.

Methods

Different concentrations of 3-MA and apatinib were used to treat the uterine sarcoma cell lines (MES-SA and FU-MMT-1 cells). The cell viability was detected by CCK8 method. Flow cytometry was used to detect the apoptosis and cell cycle. Wound closure assay and Transwell assay were performed to measure the migration ability of cells. Western blot was used to determine the apoptosis proteins and autophagy proteins. A nude mice sarcoma xenograft model was established and treated with apatinib alone, 3-MA alone, or combined incubation of them. Tumor size of xenograft and the mice survival rate were measured.

Results

Combination of 3-MA and apatinib significantly inhibited the proliferation and migration ability, but increased the apoptosis rate of uterine sarcoma cells compared to apatinib. The combination of 3-MA and apatinib significantly limited the tumor size of xenograft and increased the survival rate of mice compared to apatinib alone. Apatinib inhibited the PI3K/Akt/mTOR pathway, while 3-MA and the combination of 3-MA and apatinib significantly activated the PI3K/Akt/mTOR pathway and inhibited autophagy. Combination of 3-MA and apatinib increased apoptosis compared to apatinib alone. The expression of VEGFR-2 was not impacted by 3-MA.

Conclusion

Combination of apatinib and autophagy inhibitor 3-MA significantly inhibited the growth and migration of uterine sarcoma cells and xenograft. Autophagy inhibition may increase the antitumor effect of apatinib via the PI3K/Akt/mTOR pathway.

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Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

3-MA:

3-Methyladenine

CCK8:

Cholecystokinin 8

PI3K:

Phosphatidylinositol 3-kinase

mTOR:

Mammalian Target of Rapamycin

VEGF:

Endothelial growth factor

VEGFR-2:

Endothelial growth factor receptor 2

FBS:

Fetal bovine serum

DMEM:

Dulbecco's Modified Eagle Medium

SD:

Standard deviation

SDS:

Sodium dodecyl sulfate

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

APA:

Apatinib

ANOVA:

One-way analyses of variance

ABCB1:

P-glycoprotein 1

ABCG2:

ATP-binding cassette transporter G2

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Funding

The work was supported by Hebei Provincial Department of Science and Technology (No. 182777246).

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Authors and Affiliations

  1. Department of Gynecology, Fourth Hospital of Hebei Medical University, No.12, Jiankang Road, Shijiazhuang, 050011, Hebei, China

    Shucheng Chen & Lan Yao

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  1. Shucheng Chen
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  2. Lan Yao
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Contributions

Shucheng Chen performed the study and wrote the paper; Lan Yao designed the study, revised the paper and provided the funding.

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Correspondence to Lan Yao.

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No potential conflict of interest relevant to this article was reported.

Ethical approval

The study was approved by Ethics Committee of Fourth Hospital of Hebei Medical University (No. FHHMU-2018265).

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Chen, S., Yao, L. Autophagy inhibitor potentiates the antitumor efficacy of apatinib in uterine sarcoma by stimulating PI3K/Akt/mTOR pathway. Cancer Chemother Pharmacol 88, 323–334 (2021). https://doi.org/10.1007/s00280-021-04291-5

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  • DOI: https://doi.org/10.1007/s00280-021-04291-5

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