Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has overcome the acquired resistance of first- and second-generation EGFR-TKIs due to the EGFR T790M mutation in non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib remains a significant clinical challenge. Luteolin, a natural flavonoid from traditional Chinese medicine, has exerted antitumor effects in various tumors. In this study, we investigated whether the natural flavonoid luteolin can enhance the antitumor effects of osimertinib in NSCLC cells. We established an acquired osimertinib-resistant cell line, H1975/OR, and evaluated the effects of luteolin and osimertinib alone and in combination on proliferation, migration, invasion, and apoptosis of H1975/OR cells. The potential mechanisms by which the combination of luteolin and osimertinib exert their effects were investigated by PCR, western blot, gene silencing, molecular docking, SPR and kinase activity analysis. The combination of luteolin and osimertinib inhibited the proliferation, migration, and invasion of H1975/OR cells and promoted apoptosis. We identified mesenchymal-epithelial transition factor (MET) amplification and overactivation as important resistance mechanisms of H1975/OR cells. The combination downregulated the gene and protein expression of MET and inhibited its protein phosphorylation, thereby blocking the activation of the downstream Akt pathway. Additionally, the mediated effects of MET on the synergistic effect of luteolin and osimertinib were confirmed by silencing of MET. Luteolin strongly bound with nonphosphorylated MET by occupying the active pocket of MET and inhibiting its activation. Notably, the combination also downregulated the expression of autocrine hepatocyte growth factor (HGF), the sole ligand of MET. In conclusion, luteolin can synergize with osimertinib to overcome MET amplification and overactivation-induced acquired resistance to osimertinib by suppressing the HGF-MET-Akt pathway, suggesting the clinical potential of combining luteolin with osimertinib in NSCLC patients with acquired resistance.

Quercetin inhibits DNA damage responses to induce apoptosis via SIRT5/PI3K/AKT pathway in non-small cell lung cancer.

SIRT5 is a mitochondrial NAD+ -dependent lysine deacylase. Downregulation of SIRT5 has been linked to several primary cancers and DNA damage. In clinical therapy for non-small cell lung cancer (NSCLC), the Feiyiliu Mixture (FYLM) is an experience and effective Chinese herb prescription. And we found that quercetin is an important ingredient in the FYLM. However, whether quercetin regulates DNA damage repair (DDR) and induces apoptosis through SIRT5 in NSCLC remains unknown. The present study revealed that quercetin directly binds to SIRT5 and inhibits the phosphorylation of PI3K/AKT through the interaction between SIRT5 and PI3K, thus inhibiting the repair process of homologous recombination (HR) and non-homologous end-joining (NHEJ) in NSCLC, which raise mitotic catastrophe and apoptosis. Our study provided a novel mechanism of action of quercetin in the treatment of NSCLC.

K Value: An Indicator that can Characterize the Cold and Hot Properties of Traditional Chinese Medicines.

Aims: The cold and hot properties of Chinese medicines are an important concept to represent the function of drugs, and are also a unique classification method of traditional Chinese medicine (TCM). The method reflects an herb's therapeutic properties and guides reasonable clinical prescription. However, the present key problem is the lack of an objective and quantitative evaluation index for the cold and hot properties of Chinese herbs. Delayed luminescence (DL) is the long-term afterglow of biological systems after illumination with light, which can reflect differences in herbal materials prepared under different conditions. We aim to use S. obliquus as an indicator organism to characterize the differences between the cold and hot properties of Chinese herbs. Methods: Scenedesmus obliquus (S. obliquus) was used as an indicator organism to characterize the differences between the cold and hot properties of Chinese herbs. The decoction solution of different properties of Chinese herbs was added to S. obliquus culture medium; then, the delayed luminescence (DL) of S. obliquus after the addition of decoctions of different properties of Chinese herbs was measured to obtain information on the effect of different properties of Chinese herbs on S. obliquus. Many DL parameters were calculated, and ROC curve analysis was applied with the aim of finding a suitable parameter that can characterize the differences in cold and hot properties of Chinese herbs. Results: Our results show that the K value is a sensitive parameter that can reflect the differences of cold and hot properties of Chinese herbs, thus providing new insights into the cold and hot properties of Chinese herbs. Conclusions: DL measurement of S. obliquus after addition of different properties of Chinese herbs could be a novel and promising method to study the cold and hot properties of Chinese herbs.

Characterization of the hot and cold medicinal properties of traditional Chinese herbs by spontaneous photon emission ratio of mice.

ETHNOPHARMACOLOGICAL RELEVANCE: One important therapeutic characteristic of traditional Chinese medicine (TCM) for its properly-guided clinical prescription is considering the cold and hot medicinal properties of traditional Chinese herbs. According to the TCM theory, the hot and cold medicinal properties are defined by the general responses of a human body to a given herbal medicine. This definition is subjective and ambiguous which attenuates the modernization of TCM. Biological spontaneous photon emission (SE) is a normal phenomenon reflecting the transition of the quantum state of molecules inside an organism. The alteration of its level can indicate the changes of many aspects of the organism including metabolism. Thus, we can exploit this feature to develop a novel and scientific approach to quantitively and objectively characterize the hot and cold medicinal properties of traditional Chinese herbs. OBJECTIVE: To determine whether SE can be used to characterize the hot and cold medicinal properties of traditional Chinese herbs, this study took advantage of the ultra-weak luminescence detection technology to examine the effects of traditional Chinese herbs with hot or cold medicinal property to the level of SE in mice. MATERIALS AND METHODS: Mice were intragastrically administered with twenty traditional Chinese herbs harboring cold or hot property for ten consecutive days respectively. During the course of treatment, SE intensity of the abdomen and the back of each individual mouse were measured and recorded. At the end of the treatment, the total antioxidant capacity, superoxide dismutase activity, Na+-K+-ATPase activity and Ca2+-Mg2+-ATPase activity in the liver of all mice were examined. RESULTS: Ratio between the SE intensity of the abdomen and back of mice (defined as SE ratio) was able to distinguish the cold and hot medicinal properties of traditional Chinese herbs. Mice treated with hot herbs and cold herbs have higher and lower SE ratios respectively compared with control mice. Furthermore, levels of selected biochemical indexes in the liver were correlated with most of the SE ratio changes induced by herbal treatment. CONCLUSIONS: We have developed a novel and promising approach to quantitatively investigate herbal properties and we propose that SE ratio defined in this study can serve as a sensitive parameter to characterize the cold and hot medicinal properties of traditional Chinese herbs.