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

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.

• Authors: Shucheng Chen, Lan Yao
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 88 Issue 2 Pg. 323-334 (08 2021) ISSN: 1432-0843 [Electronic] Germany
• PMID: 33978839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Pyridines
• apatinib
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridines (pharmacology)
• Sarcoma (drug therapy, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Uterine Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays (methods)