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Dithiolation indolizine exerts viability suppression effects on A549 cells via triggering intrinsic apoptotic
Guanting Li1, Xianwei Wu1, Peng Sun2
1School of Biosciences & Biopharmaceutics and Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou 510006, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Abstract:
Indolizine derivatives have been reported for the treatment of numerous diseases. However, few studies were carried out for non-small cell lung cancer (NSCLC). We synthesized series of indolizine compounds. The results of MTT assay showed compound 8 (C8) markedly inhibited the proliferation of A549 cells, however, C8 (15, 30 μg/mL) had little cytotoxicity in other cell lines (SH-SY5Y, HepG2, and BEAS-2B cells), Hoechst staining and JC-1 staining showed that C8 induced changes in the nucleus morphology, increased the loss in mitochondrial membrane potential in A549 cells. The results of flow cytometry manifested that cell cycle of the cells was arrested in the G2 / M phase by C8, ROS levels and the proportion of apoptosis of cells increased. We performed western blotting analysis to detect the expression levels of apoptosis and cycle-related proteins. These results validated that the apoptosis of cells was triggered by endoplasmic reticulum stress (ERS) and the PI3K/Akt-mediated mitochondrial pathway collaboratively. Besides, the utilization of PI3K/Akt inhibitors and p53 inhibitors further proves the above argument and C8-induced cycle arrest of A549 cells is majorly regulated by p53. C8 induced the accumulation of ROS contents involved in mitochondrial damage. The proliferation of A549 cells was inhibited after treatment with the compound, which induced apoptosis and cycle arrest of cells. It is suggested that C8(dithiolation indolizine) is a potential candidate compound against non-small cell lung cancer.
Insights
A novel indolizine compound, C8, effectively inhibits non-small cell lung cancer (NSCLC) cell proliferation. C8 induces apoptosis and cell cycle arrest via endoplasmic reticulum stress and mitochondrial pathways, suggesting its potential as an NSCLC therapeutic.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Indolizine derivatives show therapeutic potential across various diseases.
- Research on indolizine compounds for non-small cell lung cancer (NSCLC) remains limited.
Purpose of the Study:
- To synthesize and evaluate novel indolizine derivatives for NSCLC treatment.
- To elucidate the mechanism of action of the most potent compound against NSCLC cells.
Main Methods:
- Synthesis of indolizine compounds and MTT assay for proliferation inhibition.
- Cellular and molecular analyses including Hoechst/JC-1 staining, flow cytometry, and western blotting.
- Inhibition assays using PI3K/Akt and p53 inhibitors.
Main Results:
- Compound 8 (C8) significantly inhibited A549 NSCLC cell proliferation with minimal cytotoxicity to other cell lines.
- C8 induced nuclear morphological changes, mitochondrial membrane potential loss, G2/M phase cell cycle arrest, increased ROS levels, and apoptosis.
- Apoptosis was mediated by endoplasmic reticulum stress and the PI3K/Akt mitochondrial pathway, with p53 playing a key regulatory role in cell cycle arrest.
Conclusions:
- C8 demonstrates significant anti-NSCLC activity by inducing apoptosis and cell cycle arrest.
- The compound's mechanism involves ROS generation, mitochondrial damage, ER stress, and p53-regulated pathways.
- Dithiolation indolizine C8 represents a promising candidate for NSCLC therapy.
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