Anlotinib Overcomes Multiple Drug Resistant Colorectal Cancer Cells via Inactivating PI3K/AKT Pathway

(E-pub Abstract Ahead of Print)

Author(s): Weilan Lan, Jinyan Zhao, Wujin Chen, Haixia Shang, Jun Peng, Jiumao Lin*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

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Abstract:

Background: Anlotinib is a multi-target tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the mechanisms of how anlotinib mediates drug-resistance of colorectal cancer have not been fully described. Particularly the potential mechanisms regarding to the inhibition of proliferation and induction of apoptosis remain unknown.

Objective: In this study, we intended to study the effect and related-mechanism of the proliferation, migration, invasion and induced apoptosis of anlotinib overcoming multidrug resistant colorectal cancer cells through in vitro experiments.

Methods: Cell viability was determined by MTT assays and the resistant index was calculated. Colony formation and PI/RNase Staining were used for testing the proliferation of resistant cells. DAPI staining and Annexin V-FITC/PI staining were used to detect cell apoptosis. Migration and invasion were examined by transwell. Protein expression and activation of PI3K/AKT pathway were detected by western blot. LY294002 was used to verify whether anlotinib overcomes the drug-resistance of CRC cells by inactivating the PI3K/AKT pathway.

Results: The results showed that the HCT-8/5-FU cells were resistant to multiple chemotherapy drugs (5-FU, ADM and DDP). Anlotinib significantly inhibited the cell viability, proliferation, migration, invasion and induced the cell apoptosis. Moreover, anlotinib downregulated the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, MMP-9, vimentin and N-cadherin, but up-regulated cleaved-caspase-3, Bax and E-cadherin and blocked the activity of the PI3K/AKT in HCT-8/5-FU cells. We found anlotinib and LY294002 overcame the drug resistance of HCT-8/5-FU cells by reducing the expression of PI3K/p-AKT.

Conclusions: Anlotinib inhibited the proliferation, migration, invasion and induced apoptosis of HCT-8/5-FU cells, and the mechanisms may be that anlotinib conquered multidrug resistance of colorectal cancer cells via inactivating of PI3K/AKT pathway.

Keywords: Anlotinib, colorectal cancer, multiple drug resistance, proliferation, apoptosis, migration, invasion, PI3K/AKT pathway.

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Article Details

(E-pub Abstract Ahead of Print)
DOI: 10.2174/1871520621666210112113852
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