guaiol and Carcinoma--Non-Small-Cell-Lung

(-)-Guaiol is a sesquiterpenoid found in many traditional Chinese medicines with potent antitumor activity. However, its therapeutic effect and mechanism in non-small cell lung cancer (NSCLC) have not been fully elucidated. In this study, (-)-Guaiol was found to induce immunogenic cell death (ICD) in NSCLC in vitro. Using (-)-Guaiol in vivo, we found that (-)-Guaiol could suppress tumor growth, increase dendritic cell activation, and enhance T-cell infiltration. Vaccination experiments suggest that cellular immunoprophylaxis after (-)-Guaiol intervention can suppress tumor growth. Previous studies have found that (-)-Guaiol induces apoptosis and autophagy in NSCLC. Apoptosis and autophagy are closely related to ICD. To explore whether autophagy and apoptosis are involved in (-)-Guaiol-induced ICD, we used inhibitors of apoptosis and autophagy. The results showed that the release of damage-associated molecular patterns (DAMPs) was partly reversed after inhibition of apoptosis and autophagy. In conclusion, these results suggested that the (-)-Guaiol triggers immunogenic cell death and inhibits tumor growth in NSCLC.

Topics: Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Immunogenic Cell Death; Lung Neoplasms

(-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I. Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485. Afterwards, results from biofunctional assays, including cell survival analysis, colony formation assays and flow cytometry assays, suggested that (-)-Guaiol triggered autophagic cell death by targeting both mTORC1 and mTORC2 signaling pathways. In summary, our studies showed that (-)-Guaiol inhibited the proliferation of NSCLC cells by specifically targeting mTOR signaling pathways, including both mTORC1 and mTORC2 signaling, providing a better therapeutic option for substituting rapamycin in treating NSCLC patients.

Topics: Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Humans; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 2; Models, Biological; Sesquiterpenes; Sesquiterpenes, Guaiane; Signal Transduction; TOR Serine-Threonine Kinases

(-)-Guaiol, generally known as an antibacterial compound, has been found in many medicinal plants. Its roles in tumor suppression are still under investigation. In the study, we mainly focused on exploring its applications in dealing with non-small cell lung cancer (NSCLC) and the underlying mechanisms. Here, we show that (-)-Guaiol significantly inhibits cell growth of NSCLC cells both in vitro and in vivo. Further high throughput analysis reveals that RAD51, a pivotal factor in homologous recombination repair, is a potential target for it. The following mechanism studies show that (-)-Guaiol is involved in cell autophagy to regulate the expression of RAD51, leading to double-strand breaks triggered cell apoptosis. Moreover, targeting RAD51, which is highly overexpressed in the lung adenocarcinoma tissues, can significantly increase the chemosensitivity of NSCLC cells to (-)-Guaiol both in vitro and in vivo. All in all, our studies provide an attractive insight in applying (-)-Guaiol into NSCLC treatments and further suggest that knockdown of oncogenic RAD51 will greatly enhance the chemosensitivity of patients with NSCLC.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Breaks, Double-Stranded; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lysosomes; Male; Mice; Mice, Nude; Neoplasm Transplantation; Oncogenes; Rad51 Recombinase; Recombination, Genetic; Sesquiterpenes; Sesquiterpenes, Guaiane