Journal
EXPERIMENTAL AND THERAPEUTIC MEDICINE
Volume 20, Issue 6, Pages -Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/etm.2020.9416
Keywords
colon cancer; cancer stem cells; atovaquone; hypoxia; in vitro
Categories
Funding
- Jilin Province Science and Technology Support Program [20200204036YY]
- Education Department of Jilin Province [JJKH20201122KJ]
- Jilin Province Health Technology Innovation Project [2017J062]
Ask authors/readers for more resources
Tumor hypoxia contributes to the development of resistance to chemotherapeutic drugs in several human cancer cell lines. Atovaquone, an anti-malaria drug approved by the US Food and Drug Administration, has recently demonstrated anti-cancer effects in vitro and in vivo in several cancer models. To assess the potential of atovaquone as an anti-cancer agent under hypoxia in colorectal carcinoma, EpCAM(+)CD44(+) colon cancer stem cells were isolated from HCT-116 human colon cancer cells through magnetic-activated cell sorting. The efficacy of atovaquone on cytotoxicity, tumorsphere formation, apoptosis, invasion and cell-cycle progression under hypoxic conditions were evaluated. MTS assays indicated that atovaquone inhibited the proliferation of EpCAM(+)CD44(+) HCT-116 cells with a half-maximal inhibitory concentration of 15 mu M. Atovaquone inhibited tumorsphere formation and cell proliferation by causing cell-cycle arrest in S-phase, which induced apoptosis of EpCAM(+)CD44(+) HCT-116 cells, as detected by Annexin V-FITC/PI double staining assays, and caused mitochondrial membrane potential depolarization, as determined by a JC-1 staining assay. Reverse transcription-quantitative PCR demonstrated increased expression of Bax and downregulation of Bcl-2. Transwell invasion assays indicated that atovaquone inhibited the invasiveness of EpCAM(+)CD44(+) HCT-116 cells under hypoxia, which was associated with upregulation of MMP-2 and -9 and increased expression of tissue inhibitor of MMPs (TIMP)-1. Taken together, atovaquone reduced the tumorsphere formation and invasion ability of EpCAM(+)CD44(+) HCT-116 cells, at least in part by increasing the expression of TIMP-1 and downregulating the expression of MMP-2 and -9, as well as the cells' viability by inducing cell-cycle arrest in S-phase and induction of apoptosis via the Bcl-2/Bax pathway under hypoxic conditions. Further studies are warranted to explore the mechanisms of action of atovaquone as a promising anticancer agent in the treatment of colorectal carcinoma.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available