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Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro
Published on: July 17, 2018
SL4, a chalcone-based compound, induces apoptosis in human cancer cells by activation of the ROS/MAPK signalling
1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Objectives:
SL4, a chalcone-based compound, exhibits clearly inhibitory effects on HIF-1 and has been shown to effectively suppress tumour invasion and angiogenesis in vitro and in vivo. Here, studies were conducted to determine SL4's anti-apoptotic effects and its underlying mechanisms, in human cancer cells.
Materials And Methods:
Cytotoxicity, apoptotic induction and its involved mechanisms of SL4 were investigated using normal cells, cancer cells and mouse xenograft models. The role of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) signalling in SL4-induced apoptosis was explored by manipulating specific scavenger or signalling inhibitors, in cultured cells.
Results:
SL4 significantly inhibited cell population growth of human cancer cell lines but exhibited lower cytotoxicity against normal cells. In addition, SL4 effectively induced apoptosis of Hep3B and MDA-MB-435 cells by activating procaspase-8, -9 and -3, and down-regulating expression levels of XIAP, but did not affect HIF-1 apoptosis-related targets, Survivin and Bcl-XL. Further study showed that SL4 also reduced mitochondrial membrane potential and promoted generation of ROS. ROS generation and apoptotic induction by SL4 were blocked by NAC, a scavenger of ROS, suggesting SL4-induced apoptosis via ROS accumulation. We also found that MAPKs, JNK and p38, but not ERK1/2, to be critical mediators in SL4-induced apoptosis. SP600125 and SB203580, specific inhibitors of JNK kinase and p38 kinase, significantly retarded apoptosis induced by SL4. Moreover, anti-oxidant NAC blocked activation of JNK and p38 induced by SL4, indicating that ROS may act as upstream signalling of JNK and p38 activation. It is noteworthy that animal studies revealed dramatic reduction (49%) in tumour volume after 11 days SL4 treatment.
Conclusions:
These data demonstrate that SL4 induced apoptosis in human cancer cells through activation of the ROS/MAPK signalling pathway, suggesting that it may be a novel lead compound, as a cancer drug candidate, with polypharmacological characteristics.
Insights
SL4, a chalcone compound, effectively induces apoptosis in human cancer cells by activating the reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) pathway. This compound shows potential as a novel cancer drug candidate with significant tumor volume reduction in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- SL4, a chalcone derivative, demonstrates inhibitory effects on HIF-1, suppressing tumor invasion and angiogenesis.
- Previous studies established SL4's anti-tumorigenic properties in vitro and in vivo.
Purpose of the Study:
- To investigate the anti-apoptotic effects of SL4 in human cancer cells.
- To elucidate the underlying molecular mechanisms of SL4-induced apoptosis.
Main Methods:
- Cytotoxicity assays were performed on normal and cancer cell lines.
- Apoptotic induction and its mechanisms were studied using Western blotting and flow cytometry.
- The roles of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) pathways were assessed using scavengers and inhibitors.
Main Results:
- SL4 inhibited cancer cell growth with lower toxicity to normal cells.
- SL4 induced apoptosis by activating caspases and down-regulating XIAP, reducing mitochondrial membrane potential and increasing ROS.
- ROS accumulation and subsequent activation of JNK and p38 MAPKs were identified as key mediators of SL4-induced apoptosis, with significant tumor volume reduction observed in vivo.
Conclusions:
- SL4 induces apoptosis in human cancer cells via the ROS/MAPK signaling pathway.
- SL4 exhibits polypharmacological characteristics, suggesting its potential as a novel cancer drug candidate.
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