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Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells.

ABSTRACT: Apatinib, a new-generation oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway, shows favorable therapeutic effects in various malignant tumors. However, its effect on ovarian cancer has not yet been characterized. Here, we demonstrated that apatinib inhibited ovarian cancer cell growth and migration in a concentration-dependent manner. Further, we found that apatinib could directly act on tumor cells and promote ROS-dependent apoptosis and autophagy. Mechanistically, we showed that apatinib suppressed glutathione to generate ROS via the downregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and maintained an antitumor effect at a low level of VEGFR2 in ovarian cancer, suggesting that combination of apatinib with Nrf2 inhibitor may be a promising therapy strategy for patients with ovarian cancer.

SUBMITTER: Sun X

PROVIDER: S-EPMC7244982 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells.

Sun Xiaodan X Li Ji J Li Yizhuo Y Wang Shouhan S Li Qingchang Q

Oxidative medicine and cellular longevity 20200513

Apatinib, a new-generation oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway, shows favorable therapeutic effects in various malignant tumors. However, its effect on ovarian cancer has not yet been characterized. Here, we demonstrated that apatinib inhibited ovarian cancer cell growth and migration in a concentration-dependent manner. Further, we found that apatinib could directly act on tumor cells and promote ROS-dependent apo ...[more]

PMID: 32509141

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Project description:Simple Summary AF8c, a lapatinib hybrid quinazoline-based EGFR/HER2 inhibitor, was chosen to scrutinize its antiproliferative activity in colorectal cancer (CRC) cells. We found that AF8cinduced apoptosis in CRC cells via diverse mechanisms. In addition to inhibiting the phosphorylation of the ErbB family, AF8c increased the mRNA and protein levels of death receptor 5 (DR5) in vitro and in vivo. In addition, AF8c upregulated several ER stress proteins and the redox-sensitive nuclear respiratory factor 2 alpha subunit (Nrf2) in a p53-dependent manner. We also found that the AF8c-induced increase in the levels of Nrf2, DR5, and apoptosis was diminished by p53 downregulation or knockdown. Furthermore, AF8c showed higher antiproliferative activity than lapatinib in the CRC mouse model in vivo. Therefore, our results suggest AF8c as a highly effective polypharmacological small molecule with an encouraging safety profile, both in vitro and in vivo, for further evaluation as a treatment of CRC. Abstract Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC.

Project description:OBJECTIVE:To investigate the inhibitory effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI) HS-10296 on the proliferation of triple-negative breast cancer (TNBC) MDA-MB-231 cells and explore the possible molecular mechanism. METHODS:MDA-MB-231 cells were treated with HS-10296 for 24, 48, or 72 h, and CCK-8 assay was used to assess the changes in the cell viability. The inhibitory effect of HS-10296 on cell proliferation was determined by clonogenic assay. JC-1 and flow cytometry were employed for analyzing the cell apoptosis, and the ultrastructure of the cells was observed under electron microscope. After pretreatment with autophagy inhibitor chloroquine (CQ), MDA-MB-231 cells were divided into control group, CQ treatment group, HS-10296 (4 and 6 ?mol/L) treatment groups and combined treatment groups, and the sensitivity of the treated cells to HS-10296 was determined using CCK-8 assay. The effects of HS-10296 on EGFR pathway and apoptosis- and autophagy-related proteins in MDA-MB-231 cells were investigated using Western blotting. RESULTS:HS-10296 significantly inhibited the proliferation of MDA-MB-231 cells with IC50 values at 24, 48 and 72 h of 8.393, 2.777 and 2.016 ?mol/L, respectively. JC-1 and flow cytometry showed that HS-10296 induced obvious apoptosis of MDA-MB-231 cells, which showed an apoptosis rate of (21.63 ± 2.97)% following treatment with 8 ?mol/L HS-10296. Autophagy vesicles were observed in the cells treated with HS-10296 under electron microscope. In MDA-MB-231 cells pretreated with CQ, inhibition of autophagy significantly enhanced HS-10296-induced cell death. Western blotting showed that the apoptosis-related protein caspase-3 was activated after HS-10296 treatment to cut its substrate PARP. The expression of autophagy-related protein light chain 3B (LC3B) was significantly enhanced after HS-10296 treatment (P < 0.01), which also resulted in inhibited phosphorylation of EGFR and AKT proteins in the cells. CONCLUSIONS:HS-10296 can inhibit the proliferation and induce autophagy and apoptosis of MDA-MB-231 cells by inhibiting the EGFR/PI3K/AKT signaling pathway.

Dataset Information

Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells.

Publications

Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells.

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