xanthatin and Lung-Neoplasms

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Glucose Transporter Type 1; Humans; Lung Neoplasms; Reactive Oxygen Species

Lung cancer is the cancer with the highest mortality, and non-small cell lung cancer (NSCLC) accounts for more than 80%. Tumor cells often have high reactive oxygen species (ROS) and antioxidant capacity. Redox balance is very important for tumor. The decline of antioxidant capacity and excessive ROS will induce the death of tumor cells. Destroying the redox balance of tumor cells is a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. We observed that xanthatin induced the up regulation of mitochondrial ROS and mitochondrial damage. Meanwhile, our results showed that xanthatin could inhibit system x

Topics: Acetylcysteine; Antioxidants; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Furans; Humans; Lung Neoplasms; Oxidation-Reduction; Reactive Oxygen Species

Xanthatin (Xa) is a bicyclic sesquiterpene lactone identified from the plant Xanthium L. with impressive antitumor activity, but the role of Xa in non-small cell lung cancer (NSCLC) is not known. Here we found that Xa inhibits proliferation, migration, invasion and induces apoptosis in NSCLC cells. RNA sequencing and Gene set enrichment analysis revealed that Xa significantly activates p53 pathway and suppresses E2F targets, G2M checkpoint and MYC targets in A549 cells. Among these changed genes, the down-regulated gene BARD1 triggered by Xa was identified as a candidate involved in Xa's antitumor effect because of its vital role in homologous recombination (HR). Further studies demonstrated that Xa inhibits HR through the BARD1/BRCA1/RAD51 axis, which enhances cell sensitivity to cisplatin. Mechanistic studies showed that Xa inhibits BARD1 through the JAK2/STAT4 pathway. Our study revealed that Xa is a promising drug to treat NSCLC, especially in combination with conventional chemotherapy.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cisplatin; Furans; Homologous Recombination; Humans; Janus Kinase 2; Lung Neoplasms; Signal Transduction; STAT4 Transcription Factor; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases

Xanthatin, a xanthanolide sesquiterpene lactone isolated from Xanthium strumarium L. (Asteraceae), has prominent anti-tumor activity. Initial mechanism of action studies suggested xanthatin triggered activation of Wnt/β-catenin. We examined the effects of xanthatin on signaling pathways in A459 lung cancer cells and mouse embryonic fibroblasts to ascertain requirements for xanthatin-induced cell death and tumor growth in xenografts. Genetic inactivation of GSK-3β, but not the related isoform GSK-3α, compromised xanthatin cytotoxicity while inactivation of β-catenin enhanced xanthatin-mediated cell death. These data provide insight into how xanthatin and related molecules could be effectively targeted toward certain tumors.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Furans; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; Mice; Phosphorylation; Signal Transduction; Tumor Cells, Cultured; Xanthium

Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses prominent anticancer activity. We found that disruption of GSK3β activity was essential for xanthatin to exert its anticancer properties in non-small cell lung cancer (NSCLC), concurrent with preferable suppression of constitutive activation of STAT3. Interestingly, inactivation of the two signals are two mutually exclusive events in xanthatin-induced cell death. Moreover, we surprisingly found that exposure of xanthatin failed to trigger the presumable side effect of canonical Wnt/β-Catenin followed by GSK3β inactivation. We further observed that the downregulation of STAT3 was required for xanthatin to fine-tune the risk. Thus, the discovery of xanthatin, which has ability to simultaneously orchestrate two independent signaling cascades, may have important implications for screening promising drugs in cancer therapies.

Topics: Antineoplastic Agents; Apoptosis; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Furans; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; RNA Processing, Post-Transcriptional; STAT3 Transcription Factor

Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancer cells, yet little is known about its anticancer mechanism. In this study, we demonstrated that xanthatin had obvious dose-/time-dependent cytotoxicity against the human non-small-cell lung cancer (NSCLC) cell line A549. Flow cytometry analysis showed xanthatin induced cell cycle arrest at G2/M phase. Xanthatin also had pro-apoptotic effects on A549 cells as evidenced by Hoechst 33258 staining and annexin V-FITC staining. Mechanistic data revealed that xanthatin downregulated Chk1, Chk2, and phosphorylation of CDC2, which contributed to the cell cycle arrest. Xathatin also increased total p53 protein levels, decreased Bcl-2/Bax ratio and expression of the downstream factors procaspase-9 and procaspase-3, which triggered the intrinsic apoptosis pathway. Furthermore, xanthatin blocked phosphorylation of NF-κB (p65) and IκBa, which might also contribute to its pro-apoptotic effects on A549 cells. Xanthatin also inhibited TNFa induced NF-κB (p65) translocation. We conclude that xanthatin displays significant antitumor effects through cell cycle arrest and apoptosis induction in A549 cells. These effects were associated with intrinsic apoptosis pathway and disrupted NF-κB signaling. These results suggested that xanthatin may have therapeutic potential against NSCLC.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Dose-Response Relationship, Drug; Furans; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; NF-kappa B; Signal Transduction; Tumor Suppressor Protein p53