Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.
To screen drugs that target CSCs ...to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.
We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib.
We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.
Recently, we demonstrated that
(PG2), the active ingredient in dried roots of
ameliorates cancer symptom clusters and improves quality of life (QoL) in patients with metastatic disease by modulating ...inflammatory cascade against the background roles of inflammatory cells, including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear.
The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade and enhances anticancer immunity, as well as the therapeutic implication of these bio-events in patients with lung cancer.
Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity, and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that treatment with PG2 elicited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibited xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscrasia and weight-loss was markedly suppressed.
These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin, thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.
Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, ...from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells.
This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays.
In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells.
In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.
Intracerebral hemorrhage (ICH) is a highly harmful neurological disorder with high rates of mortality, disability, and recurrence. However, effective therapies are not currently available. Secondary ...immune injury and cell death are the leading causes of brain injury and a poor prognosis. Pyroptosis is a recently discovered form of programmed cell death that differs from apoptosis and necrosis and is mediated by gasdermin proteins. Pyroptosis is caused by multiple pathways that eventually form pores in the cell membrane, facilitating the release of inflammatory substances and causing the cell to rupture and die. Pyroptosis occurs in neurons, glial cells, and endothelial cells after ICH. Furthermore, pyroptosis causes cell death and releases inflammatory factors such as interleukin (IL)-1β and IL-18, leading to a secondary immune-inflammatory response and further brain damage. The NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway plays the most critical role in pyroptosis after ICH. Pyroptosis can be inhibited by directly targeting NLRP3 or its upstream molecules, or directly interfering with caspase-1 expression and GSDMD formation, thus significantly improving the prognosis of ICH. The present review discusses key pathological pathways and regulatory mechanisms of pyroptosis after ICH and suggests possible intervention strategies to mitigate pyroptosis and brain dysfunction after ICH.
Background
Whether non–vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin among Asians with nonvalvular atrial fibrillation remains unclear.
Methods and Results
In this ...nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, there were 5843, 20 079, 27 777, and 19 375 nonvalvular atrial fibrillation patients taking apixaban, dabigatran, rivaroxaban and warfarin, respectively, from June 1, 2012 to December 31, 2016. Propensity‐score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any efficacy or safety outcome or the end date of study. Hazard ratios (95% confidence intervals) comparing apixaban, dabigatran, and rivaroxaban with warfarin were: ischemic stroke/systemic embolism (IS/SE), 0.55 (0.43–0.69), 0.82 (0.68–0.98), and 0.81 (0.67–0.97); major bleeding, 0.41 (0.31–0.53), 0.65 (0.53–0.80), and 0.58 (0.46–0.72); and all‐cause mortality, 0.58 (0.51–0.66), 0.61 (0.54–0.68), and 0.57 (0.51–0.65). A total of 3623 (62%), 17 760 (88%), and 26 000 (94%) patients were taking low‐dose apixaban (2.5 mg twice daily), dabigatran (110 mg twice daily), and rivaroxaban (10–15 mg once daily), respectively. Similar to all‐dose NOACs, all low‐dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. In contrast to other standard‐dose NOACs, apixaban was associated with lower risks of IS/SE (0.45 0.31–0.65), major bleeding (0.29 0.18–0.46), and mortality (0.23 0.17–0.31) than warfarin.
Conclusions
All NOACs were associated with lower risk of IS/SE, major bleeding, and mortality compared with warfarin in the largest real‐world practice among Asians with nonvalvular atrial fibrillation. All low‐dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. Standard‐dose apixaban caused a lower risk of IS/SE, major bleeding, and mortality compared with warfarin.
Metastasis is one of the most important factors related to breast cancer therapeutic efficacy. Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, we ...first observed that ursolic acid exerted a dose- and time-dependent inhibitory effect on the migration and invasion of highly metastatic breast MDAMB231 cells at non-cytotoxic concentrations. This effect was associated with reduced activities of metalloproteinase-2 (MMP-2) and u-PA, which correlated with enhanced expression of tissue inhibitor of MMP-2 and plasminogen activator inhibitor-1, respectively. Ursolic acid suppressed the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin, but had no effect on the phosphorylation of ERK and p38. Ursolic acid also strongly reduced the levels of NFκB p65, c-Jun and c-Fos proteins in the nucleus of MDAMB231 cells. A time-dependent inhibition of the protein levels of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol by ursolic acid treatment was also observed. In conclusion, we demonstrated that the anti-invasive effects of ursolic acid on MDAMB231 cells might be through the inhibition of Jun N-terminal kinase, Akt and mammalian target of rapamycin phosphorylation and a reduction of the level of NFκB protein in the nucleus, ultimately leading to downregulation of MMP-2 and u-PA expression. These results suggest that ursolic acid has potential as a chemopreventive agent for metastatic breast cancer.
Abstract Background It is unclear whether the non–vitamin K antagonist oral anticoagulant agents rivaroxaban and dabigatran are superior to warfarin for efficacy and safety outcomes in Asians with ...nonvalvular atrial fibrillation (NVAF). Objectives The aim of this study was to compare the risk for thromboembolic events, bleeding, and mortality associated with rivaroxaban and dabigatran versus warfarin in Asians with NVAF. Methods A nationwide retrospective cohort study was conducted of consecutive patients with NVAF taking rivaroxaban (n = 3,916), dabigatran (n = 5,921), or warfarin (n = 5,251) using data collected from the Taiwan National Health Insurance Research Database between February 1, 2013 and December 31, 2013. The propensity score weighting method was used to balance covariates across study groups. Patients were followed until the first occurrence of any study outcome or the study end date (December 31, 2013). Results A total of 3,425 (87%) and 5,301 (90%) patients were taking low-dose rivaroxaban (10 to 15 mg once daily) and dabigatran (110 mg twice daily), respectively. Compared with warfarin, both rivaroxaban and dabigatran significantly decreased the risk for ischemic stroke or systemic embolism (p = 0.0004 and p = 0.0006, respectively), intracranial hemorrhage (p = 0.0007 and p = 0.0005, respectively), and all-cause mortality (p < 0.0001 and p < 0.0001, respectively) during the short follow-up period. In comparing the 2 non–vitamin K antagonist oral anticoagulant agents with each other, no differences were found regarding risk for ischemic stroke or systemic embolism, intracranial hemorrhage, myocardial infarction, or mortality. Rivaroxaban carried a significantly higher risk for hospitalization for gastrointestinal bleeding than dabigatran (p = 0.0416), but on-treatment analysis showed that the risk for hospitalized gastrointestinal bleeding was similar between the 2 drugs (p = 0.5783). Conclusions In real-world practice among Asians with NVAF, both rivaroxaban and dabigatran were associated with reduced risk for ischemic stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality without significantly increased risk for acute myocardial infarction or hospitalization for gastrointestinal bleeding compared with warfarin.
IMPORTANCE: Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. OBJECTIVE: To assess the ...association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. EXPOSURES: NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. MAIN OUTCOMES AND MEASURES: Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. RESULTS: Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years SD, 10.8; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 99% CI, 9.76-18.13); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 99% CI, 80.96-195.97); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 99% CI, 32.18-72.44; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone. CONCLUSIONS AND RELEVANCE: Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs.
Increasing evidence shows that hepatocellular carcinoma (HCC) is a principal cause of cancer-related mortality globally, especially among Asian and African populations. Collagen type I α1 (COL1A1) is ...the major component of type I collagen. While aberrant expression of COL1A1 and COL1A2 is implicated in numerous cancers, the differential role of COL1A1 in malignant, premalignant and normal tissues remains unclear, and its clinical significance in HCC has not been elucidated. In this study, using bioinformatics analysis of publicly-available HCC microarray data from Gene Expression Omnibus (GEO) and RNAseq data from The Cancer Genome Atlas (TCGA) database, we determined that COL1A1 is significantly upregulated in HCC tumor tissues in comparison to normal tissues. Our analysis also revealed that COL1A1 confers survival advantage and enhanced oncogenicity on HCC cells. Interestingly, the siRNA-mediated silencing of COL1A1 expression (siCOLIA1) suppressed HCC cells clonogenicity, motility, invasiveness and tumorsphere formation. Concomitantly, siCOL1A1 abrogated Slug-dependent epithelial-to-mesenchymal transition (EMT) and HCC stemness gene-signature, by attenuating expression of stemness markers SOX2, OCT4 and CD133. The present study provides some mechanistic insight into COL1A1 activity in HCC and highlights its putative role as an important diagnostic biomarker and potential therapeutic target in early development and metastasis of HCC.
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