Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer.

RATIONALE: Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance. OBJECTIVES: To screen drugs that target CSCs to improve the current treatment outcome and overcome drug resistance in patients with lung cancer. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/ß-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. CONCLUSIONS: 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.

Apical root resorption in orthodontic patients with en-masse maxillary anterior retraction and intrusion with miniscrews.

INTRODUCTION: The purposes of this retrospective study were to investigate the apical root resorption of maxillary incisors in orthodontic patients with en-masse maxillary anterior retraction and intrusion with miniscrews and the factors disposing a patient to apical root resorption. METHODS: Fifty adult patients with maxillary protrusion were included; 30 were treated with miniscrews and extraction of the maxillary first premolars (group I), and 20 were treated with extraction of the maxillary first premolars (group II). For each patient, periapical films of the maxillary incisors and lateral cephalometric radiographs were taken before and after treatment to evaluate apical root resorption and cephalometric measurements. The intergroup differences were analyzed with the Student t test and the correlations between apical root resorption and cephalometric measurements were analyzed by the Pearson correlation. RESULTS: The apical root resorption values were 16.0% to 20.0% (2.5-2.8 mm) in group I and 13.4% to 14.4% (2.1-2.3 mm) of the original root length in group II. Group I had significantly more severe Class II jaw discrepancy (ANB, 7.1 degrees +/- 1.9 degrees ) than did group II (ANB, 3.2 degrees +/- 2.9 degrees ). The amount of maxillary en-masse anterior retraction (8.2 +/- 2.4 mm), the duration of treatment (28.3 +/- 7.3 months), and apical root resorption of maxillary lateral incisors were significantly greater in group I than in group II. Apical root resorption of the maxillary central incisors was significantly correlated to the duration of treatment but not to the amount of en-masse retraction, intrusion, or palatal tipping of maxillary incisors. CONCLUSIONS: Miniscrew anchorage allows for more maxillary en-masse anterior retraction in patients with severe Class II cases. But the time needed for the greater amount of maxillary en-masse anterior retraction with miniscrew anchorage is longer and might dispose the patient to more apical root resorption.

Novel immune-modulating drugs for advanced head and neck cancer.

BACKGROUND: Recently, two anti-PD-1 immune checkpoint inhibitors, pembrolizumab and nivolumab, have been approved by the US Food and Drug Administration for patients who fail on platinum-based chemotherapy. However, overall response and progression-free survival are still limited, and multiple novel agents are under development to fulfill this unmet clinical need. METHODS: Publications between 1992 and 2019 regarding the immunological/biological mechanisms and early phase clinical trial outcomes of immunomodulatory agents for head and neck cancer were described in this review article. RESULTS: Eleven immunomodulatory agents for advanced head and neck, including small molecules, antibodies, and therapeutic vaccines were described. Treatment responses were noted in nearly all 11 agents, as monotherapy or combination therapy. CONCLUSIONS: Potentials of the novel immunomodulatory agents to improve treatment efficacy of head and neck cancer and to maintain tolerable safety profile have been disclosed.

Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer.

Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from Withania somnifera, as a potential anti-lung cancer and anti-lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC50 values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. In vivo research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.

The assessment of anticoagulant activity to predict bleeding outcome in atrial fibrillation patients receiving dabigatran etexilate.

Special circumstances may require the measurement of the anticoagulant effect of dabigatran etexilate. No data currently link any given coagulation test to bleeding outcomes in patients receiving dabigatran etexilate for atrial fibrillation. Nonvalvular atrial fibrillation patients receiving dabigatran etexilate of 110 mg (DE110) or 150 mg (DE150) were consecutively enrolled. The hemoclot thrombin inhibitor (HTI) assay, prothrombin time, and activated partial thromboplastin time (APTT) measurements were correlated with bleeding events during a prospective follow-up. There were 17 bleeding events (8.2%) in 208 patients (74.7 ±â€Š10.3 years old, 67.9% male, median follow-up: 364 days), whereas 15 patients with bleeding events used DE110. Compared with DE110, the patients receiving DE150 were younger and more often male and had lower HAS-BLED and CHA2DS2VASc scores and better renal function. Patients' HTI levels were very variable (DE110, 10-90th percentile: 20.5-223.9 ng/ml). A receiver-operator characteristic curve gave a median cutoff HTI level of 117.7 ng/ml to predict bleeding events (C-statistics: 0.65; P = 0.036), but no cutoff could be determined for prothrombin time or APTT. Based on the Kaplan-Meier analysis, a dabigatran etexilate level greater than 117.7 ng/ml was associated with a higher bleeding rate (15.4% vs. 4.9%, P = 0.01). After multivariate Cox regression analysis, HTI levels, history of stroke, and male sex were independent risk factors for bleeding events. Dabigatran etexilate-HTI levels were independently associated with bleeding in patients receiving routine clinical care. Blood sampling at multiple time points might be needed to increase reliability because of high variation of dabigatran etexilate-HTI levels.

A preclinical evaluation of antimycin a as a potential antilung cancer stem cell agent.

Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs) as the major contributor to these clinical challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP) method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs), was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA), was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, ß -catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress ß -catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate ß -catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.