Objective: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. Background: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. Methods: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. Results: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. Conclusion: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.
Background: To explore the generic association between miR-499 rs3746444 polymorphism and ischemic stroke (IS). Methods: We performed a systematic review and meta-analysis, odds ratio (OR) and 95% confidence intervals (CIs) were used to estimate the association quantitively. Results: A total of 6 studies (involving 2569 IS cases and 2645 controls) were included. miR-499 (rs3746444) polymorphism showed a statistically significant association with IS risk in the allelic model (G allele vs A allele), the dominant model (GG+AG vs AA), the recessive model (GG vs AG+AA) and the homozygote model (GG vs AA). ORs of the above 4 models were 1.20 (95%CI: 1.02, 1.40), 1.21 (95%CI: 1.01, 1.46), 1.40 (95%CI: 1.04, 1.88), 1.48 (95%CI: 1.10, 2.00) respectively. The I square of the allelic model and the dominant model was 58% and 59%, indicating large heterogeneity among included studies. By sensitivity analysis, I square of the two models dropped to 34.5% and 38.4%, the ORs were 1.26 (95%CI: 1.13, 1.42) and 1.28 (95%CI: 1.12, 1.46), there was still a statistical association between miR-499 (rs3746444) polymorphism and IS. The heterozygote model (AG vs AA) was not statistically significant, the OR was 1.18 (95%CI: 0.99, 1.42), the I square was 54%. Notably, by sensitivity analysis, I square of the heterozygote model dropped to 34.6%, the OR was 1.25 (95%CI: 1.08, 1.43), indicating a statistically significant association between miR-499 (rs3746444) polymorphism and IS. There was no publication bias for all the models by Egger's test. Conclusion: miR-499 (rs3746444) polymorphisms is associated with the increase of IS risk.
OBJECTIVE Adipocytes are the most abundant stromal partners in breast tissue. However, the crosstalk between breast cancer cells and adipocytes has been given less attention compared to cancer-associated fibroblasts. We try to explain whether cancer associate adipocytes (CAAs) in microenvironment can lead to metabolic remodeling of triple-negative breast cancer, promoted cancer proliferation, migration and the potential mechanism. METHOD A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo were used to study the crosstalk between adipocytes and breast cancer cells, and then using clinical breast cancer sample analysis to study the mechanism of glutamine reprograming. RESULTS We find that while cocultivated adipocytes with breast cancer cells, it exhibited enhanced oxygen consumption rate (OCR) and ATP, accompanied by increasing glucose and glutamine uptake. Interestingly, the metabolic way is significantly different between phenotype-specific breast cancer cells. Compared with non-triple-negative breast cancer cells, triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468) are more dependent on glutamine. We show that cancer associate adipocytes (CAAs) promote growth of breast cancer cells through key enzymes such as GLUL/GLS/GDH and transporters such as SLC1A5/SLC38A1/SLC38A2 related to glutamine metabolism in vitro. Using cytokine antibody microarrays, IL-6/IL-8/ leptin/TIPM2 is secreted by CAAs and is required to enhance breast cancer cells malignancy in vitro. Consistently, the correlation of inflammatory cytokines and adipokines with prognosis is analyzed by the Kaplan-Meier plotter, the data suggest that inflammatory cytokines and adipokines is associated with glutamine metabolism in triple-negative breast cancer microenvironment. CONCLUSIONS These results suggest that adipocytes promote proliferation of triple-negative breast cancer via metabolism reprogramming potentially by inducing inflammatory cytokines and adipokines upregulation of cancer associate adipocytes (CAAs). Citation Format: Yang Liu, Tingli Zhao, Zhengzheng Li, Lai Wang, Mei Yang, Shengtao Yuan, Li Sun. Glutamine metabolism reprogramming in adipocyte-tumor microenvironment promotes triple-negative breast cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 387.
The aim of the present study was to explore the generic association between the miR-499 (rs3746444) polymorphism and the risk of ischemic stroke (IS). A systematic review and meta-analysis was performed, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to quantitatively estimate the association. A total of 8 studies (involving 3,400 IS cases and 3,652 controls) were included in the present meta-analysis. The results of the allelic model (G allele vs. A allele) revealed a statistically significant association between the miR-499 (rs3746444) polymorphism and the risk of IS; the OR was 1.16 (95% CI, 1.00-1.34; P<0.05). Similarly, the results of the recessive model (GG vs. AG + AA), the heterozygote model (AG vs. AA) and the homozygote model (GG vs. AA) were statistically significant; the ORs were 1.36 (95% CI, 1.05-1.77; P<0.05), 1.11 (95% CI, 1.00-1.23; P<0.05) and 1.42 (95% CI, 1.09-1.86; P<0.05), respectively. However, the dominant model (GG + AG vs. AA) did not exhibit any significant differences; the OR was 1.16 (95% CI, 0.99-1.36; P>0.05). The results of the Q test indicated that the heterogeneity of the allelic model (I 2 =63%, P=0.01), as well as that of the dominant model (I 2 =60%, P=0.02), was relatively large. Subsequently, a sensitivity analysis was performed; the I 2 of each model then decreased to <50%. Notably, by sensitivity analysis, both the allelic model and the dominant model exhibited a statistically significant association between the miR-499 (rs3746444) polymorphism and the risk of IS. Egger's test did not reveal any publication bias for any of the models. On the whole, the present study demonstrates that the miR-499 (rs3746444) polymorphism may contribute to an increased risk of IS.
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