Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer

Kim, Han Sol; Oh, Han-Mo; Kwak, Ah-Won; Kim, Eunae; Lee, Mee-Hyun; Seo, Jeong‐Meen; Cho, Seung‐Sik; Yoon, Goo; Chae, Jung‐Il; Shim, Jung‐Hyun

doi:10.4014/jmb.2101.01029

Cited by 12 publications

(12 citation statements)

References 31 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2021, Kim used DPT to treat non-small cell lung cancer (NSCLC) and found that DPT could suppress the expression of p -EGFR and p-MET as well as their downs treat proteins p -ErbB3, p -AKT, and p -ERK, and induced high ROS generation. 97…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

et al. 2022

View full text Add to dashboard Cite

show abstract

Section: Pharmacological Activitiesmentioning

confidence: 99%

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

et al. 2022

View full text Add to dashboard Cite

show abstract

“…It is well known that the most common hallmarks of cancer cells include sustained proliferation and attenuated apoptosis ( Hanahan and Weinberg, 2011 ). Lately, research has shown that deoxypodophyllotoxin plays an important role in acquired resistance to gefitinib by inducing apoptosis in NSCLC cells ( Kim et al, 2021 ). Consistent with the results, in our study, FYLM downregulated the expression of the apoptosis-related protein Bcl-2 while upregulating the cleaved caspase-3 in a mouse xenograft model.…”

Section: Discussionmentioning

confidence: 99%

Feiyiliu Mixture sensitizes EGFRDel19/T790M/C797S mutant non-small cell lung cancer to osimertinib by attenuating the PRC1/Wnt/EGFR pathway

et al. 2023

View full text Add to dashboard Cite

Introduction: Osimertinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of acquired resistance due to the EGFR-Del19/T790M/C797S mutation limits the clinical application of osimertinib. Feiyiliu Mixture (FYLM), a clinical experience formula of Chinese medicine, was used to treat lung cancer with good clinical efficacy. In this study, we aimed to investigate the mechanism by which Feiyiliu Mixture delays osimertinib resistance in EGFR-mutant cell lines and EGFR-mutant cell tumor-bearing mice.Methods: The osimertinib-resistant cell models were established in mouse Lewis lung carcinoma (LLC) cells transfected with EGFR-Del19/T790M/C797S mutant lentivirus. In cell experiments, after 48 h of treatment with Feiyiliu Mixture-containing serum, MTT assay was used to detect the relative cell viability, and western blotting was used to detect EGFR protein phosphorylation expression. In animal experiments, C57BL/6J mice were subcutaneously injected with Lewis lung carcinoma cells stably expressing EGFR-Del19/T790M/C797S mutations to construct a xenograft model. After 2 weeks of Feiyiliu Mixture and/or osimertinib treatment, the expression of proliferation-related, apoptosis-related and PRC1/Wnt/EGFR pathway markers was detected by real-time qPCR, western blotting and immunohistochemistry.Results: The results showed that when combined with osimertinib, Feiyiliu Mixture synergistically reduces proliferation and increases apoptosis to improve drug resistance. In vitro, Feiyiliu Mixture-containing serum reduced the EGFR phosphorylation. In vivo, Feiyiliu Mixture downregulated the expression of cyclin B1 and Bcl-2 while upregulating the level of cleaved Caspase-3 protein, indicating that Feiyiliu Mixture promotes apoptosis. Furthermore, Feiyiliu Mixture reduced the expression of p-EGFR, p-Akt, PRC1 and Wnt pathway-related proteins such as β-catenin, c-Myc and c-Jun.Conclusion: The present study identified that Feiyiliu Mixture inhibited PRC1/Wnt/EGFR pathway activation, reduced proliferation, and promoted apoptosis, thereby increasing the sensitivity of EGFR-mutant non-small cell lung cancer to osimertinib. Our study provided a new idea for Chinese medicine to play a role in enhancing efficacy and reducing toxicity in the treatment of non-small cell lung cancer.

show abstract

“…Many studies have displayed that triggering mitochondria-mediated apoptosis becomes an available method for therapy of resistant cancer. In addition, mitochondria dysfunction could cause the generation of intracellular ROS ( Kim et al, 2021 ), which is confirmed to be involved in the drug resistance related to EGFR and its downstream pathway ( Weng et al, 2018 ; Zhang et al, 2019 ). Excessive ROS produced by external stimuli was not conducive to the survival of cells, thus causing the accumulation of ROS and cell apoptosis ( Yuan et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“… Young et al (2016) reported that Simvastatin can induce mitochondrial apoptosis to overcome gefitinib resistance with EGFR T790M mutation NSCLC cells. As well known, reactive oxygen species (ROS) formation is closely related to the mitochondrial pathway, which is confirmed to be the cause and/or consequence of the mitochondrial dysfunction ( Kim et al, 2021 ). High levels of ROS triggers oxidant stress, which leads to cellular damages, tumor progression, and chemotherapy resistance ( Brozovic et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

et al. 2022

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as a first-line treatment for patients harboring with EGFR mutations in advanced NSCLC. Nevertheless, the drug resistance after continuous and long-term chemotherapies considerably limits its clinical efficacy. Therefore, it is of great importance to develop new chemotherapeutic agents and treatment strategies to conquer the drug resistance. FGFC1 (Fungi fibrinolytic compound 1), a type of bisindole alkaloid from a metabolite of the rare marine fungi Starchbotrys longispora. FG216, has exhibited excellent fibrinolytic and anti-inflammatory activity. However, the potent efficacy of FGFC1 in human cancer therapy requires further study. Herein, we demonstrated that FGFC1 selectively suppressed the growth of NSCLC cells with EGFR mutation. Mechanistically, FGFC1 treatment significantly induced the apoptosis of erlotinib-resistant NSCLC cells H1975 in a dose-dependent manner, which was proved to be mediated by mitochondrial dysfunction and elevated accumulation of intracellular reactive oxygen species (ROS). Scavenging ROS not only alleviated FGFC1-induced apoptosis but also relieved the decrease of phospho-Akt. We further confirmed that FGFC1 significantly decreased the phosphorylation of protein EGFR, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in H1975 cells. Notably, PI3K inhibitor (LY294002) could promote the accumulation of ROS and the expression levels of apoptosis-related proteins induced by FGFC1. Molecular dynamics simulations indicated that FGFC1 can inhibit EGFR and its downstream PI3K/Akt/mTOR pathway through directly binding to EGFR, which displayed a much higher binding affinity to EGFRT790M/L858R than EGFRWT. Additionally, FGFC1 treatment also inhibited the migration and invasion of H1975 cells. Finally, FGFC1 effectively inhibited tumor growth in the nude mice xenograft model of NSCLC. Taken together, our results indicate that FGFC1 may be a potential candidate for erlotinib-resistant NSCLC therapy.

show abstract

Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer

Cited by 12 publications

References 31 publications

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

Feiyiliu Mixture sensitizes EGFRDel19/T790M/C797S mutant non-small cell lung cancer to osimertinib by attenuating the PRC1/Wnt/EGFR pathway

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

Contact Info

Product

Resources

About