Xuesong Lu

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium (commonly known as Shihu in China), a traditional Chinese medicinal herb recognized in the Pharmacopoeia of China (2020 edition), boasts a rich history of medicinal application. Extensive research has been conducted on its Chinese medicinal prescription due to its demonstrated anti-tumour effects in clinical settings. Dendrobium is comprised of a diverse range of chemical compounds, notably the Bibenzyls, Erianin, and Gigantol, which have exhibited significant inhibitory and therapeutic effects on cervical cancer, thereby suggesting potential therapeutic value. However, the comprehensive investigation of Chrysotoxine, a naturally occurring active ingredient of Bibenzyls in Dendrobium, remains incomplete in treatment of cervical cancer. AIMS OF THE STUDY: This study aimed to conduct a comprehensive investigation of Chrysotoxine and its regulatory impact on ferroptosis in cervical cancer. MATERIALS AND METHODS: Initially, the effects of chrysotoxine on the cervical cancer cell line HeLa were assessed using CCK-8, transwell, colony formation, and flow cytometry to evaluate cell proliferation, invasion, migration, and apoptosis. Subsequently, network pharmacology and molecular docking techniques were employed to identify the molecular targets of chrysotoxine in cervical cancer. Finally, confocal microscopy assessed the expression levels of ROS and lipid compounds in response to chrysotoxine treatment, and the influence of chrysotoxine on signaling pathways was investigated using Western blot analysis, guided by KEGG pathway analysis. RESULTS: Our cell-based experiments revealed that CTX effectively suppresses the cell proliferation, migration, invasion, and apoptosis in CC. Subsequently, we comprehensively analyzed that HSP90AA1, ESR1, PIK3CA, mTOR and MAPK1 may be the possible targets of CTX in CC by combining network pharmacology with molecular docking techniques. Finally, we observed that CTX enhances the production of intracellular ROS and excessive lipid peroxides. Simultaneously, we detected that CTX promotes ferroptosis-based p53/GPX4/SLC7A11 pathway and inhibits PI3K/AKT/mTOR pathway-induced cell death of CC by Western blot. CONCLUSION: Our study indicates that chrysotoxine shows promise as a novel medication for treating CC. The findings provide a scientific foundation for the regulation of cervical cancer by chrysotoxine, presenting new insights into the application of traditional Chinese medicine for fighting CC.

// Di Zheng 1, * , Min Hu 2, * , Yu Bai 2 , Xuehua Zhu 2 , Xuesong Lu 3 , Chunyan Wu 4 , Jiying Wang 1 , Li Liu 1 , Zheng Wang 3 , Jian Ni 1 , Zhenfan Yang 2 and Jianfang Xu 1 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School, Shanghai, China 2 IMED Asia, AstraZeneca, Shanghai, China 3 Research and Development Information, AstraZeneca, Shanghai, China 4 Department of Pathology, Shanghai Pulmonary Hospital, Tongji University Medical School, Shanghai, China * These authors contributed equally to this work Correspondence to: Jianfang Xu, email: xujianfang63@aliyun.com Zhenfan Yang, email: Pamela.Yang@astrazeneca.com Keywords: EGFR, NSCLC, osimertinib, drug resistance, G796D Received: March 08, 2017      Accepted: May 04, 2017      Published: May 16, 2017 ABSTRACT Osimertinib is an effective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in multiple countries and regions for patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). Despite impressive initial tumor responses, development of drug resistance ultimately limits the benefit of this compound. Mechanisms of resistance to osimertinib are just beginning to emerge, such as EGFR C797S and L718Q mutations, BRAF V600E and PIK3CA E545K mutations, as well as ERBB2 and MET amplification. However, a comprehensive view is still missing. In this study, we presented the first case of Chinese NSCLC patient who developed resistance to osimertinib, and discovered de novo EGFR G796D mutation as a potential mechanism. Our findings provided insights into mechanisms of resistance to osimertinib and highlighted tumor heterogeneity and clonal evolution during the development of drug resistance.

Abstract Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM. Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development. Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR.