<p>Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells</p>

Abstract

Background: Irinotecan (IRI) is considered an option for second-line treatment of advanced gastric cancer; however, acquired drug resistance currently limits its clinical application. Recently, many researchers have shown that autophagy plays a crucial role in the resistance of tumor cells to chemotherapy and radiotherapy. In this study, we investigated the relationship between autophagy and antitumor activity of IRI in gastric cancer cells. Methods: We used MTT assay, flow cytometry and immunofluorescence staining to detect viability, apoptosis and autophagy in gastric cancer. Western blotting assay was used to determine the expression of LC3, Beclin-1, P62, cleaved PARP and Caspase 3. In vivo animal study was performed finally. Results: We found that IRI treatment dose-and time-dependently inhibited growth and induced apoptosis in gastric cancer cells. Moreover, IRI treatment caused autophagy in these cells, whereas autophagy inhibitors-3-methyladenine (3-MA), chloroquine (CQ), and Beclin-1 small interfering RNA (siRNA)-suppressed cytotoxicity of IRI. A mechanistic analysis showed that IRI-induced autophagy and apoptosis were related to increased reactive oxygen species (ROS) accumulation and activation of the JNK-and p38-MAPK pathways. Further in vivo experiments revealed that IRI suppressed tumor growth, induced autophagy, and stimulated the JNK-and p38-MAPK pathways, whereas 3-MA attenuated these effects. Conclusion: Taken together, these results indicate that IRI stimulates the ROS-related JNKand p38-MAPK pathways to promote autophagy-dependent apoptosis. Thus, a combination of IRI with a pharmacological autophagy enhancer may be a promising therapeutic strategy against gastric cancer.

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

“…Therefore, using agents that enhance ROS generation is improtant in providing chemosensitivity. Overall, studies are in agreement with antitumor activity of ROS and their capacity in regulating various molecular pathways [76][77][78][79][80]. However, there are controversies about the role of ROS in cancer cells.…”

Hydroxychloroquine Induces Apoptosis in Cholangiocarcinoma via Reactive Oxygen Species Accumulation Induced by Autophagy Inhibition

“…It will produce a series of toxic and side effects on various cell membrane structures in cells, resulting in cell death (Hayes et al, 2020). Zhu et al (2020) reported that administration of 20 μmol/ L irinotecan for 24 h could significantly increase the ROS content in gastric cancer cells and result in apoptosis of gastric cancer cells FIGURE 6 | HCQ induces apoptosis in cholangiocarcinoma cells in an ROS-dependent manner. Cells were preincubated with GSH (3 mmol/L) for 2 h and then treated with HCQ for 24 h. (A) ROS levels in HuCCT-1 and CCLP-1 cells treated with HCQ (IC50) and GSH were detected by flow cytometry.…”

CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death

“…have proved that SNX-2112, the Hsp90 inhibitor, enhanced TRAIL-induced apoptosis and autophagy of cervical cancer cells through activating the ROS-regulated JNK-p53-autophagy-DR5 pathway ( 26 ); Zhu et al. indicated that irinotecan (IRI) stimulated the reactive oxygen species (ROS)-related JNK- and p38-MAPK signaling pathways to increase autophagy-dependent apoptosis and inhibit growth of gastric cancer cells ( 40 ). Therefore, the active status of the JNK/c-Jun signaling pathway was detected under CASK knockdown condition in the present study.…”