Background/Aim: We investigated drugs that could sensitize P-glycoprotein (P-gp)-overexpressing drug-resistant cancer cells to vincristine (VIC) or eribulin treatment and assessed their associated mechanisms of action. Materials and Methods: We investigated 15 bipolar drugs (quetiapine, risperidone, clozapine, asenapine, iloperidone, paliperidone, ziprasidone, trifluoperazine, loxapine succinate, pilocarpine, valproic acid, carbamazepine, levetiracetam, topiramate, and felbamate) to identify drugs with a sensitizing effect on VICresistant KBV20C cells at relatively low doses. Fluorescenceactivated cell sorting (FACS), annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. Results: We found that co-treatment with half the tested drugs (quetiapine, iloperidone, trifluoperazine, loxapine, risperidone, ziprasidone, or felbamate) at low doses could highly sensitize VIC-resistant KBV20C cells. With lower amounts of the bipolar drugs or VIC, we found that among the 15 bipolar drugs tested, 2 combinations (VIC-quetiapine and VIC-trifluoperazine) had much higher sensitization effects, suggesting that lower effective doses were sufficient for sensitizing P-gp-overexpressing resistant cells compared to those required with the other drugs. Furthermore, when we compared quetiapine and trifluoperazine to previously known bipolar drugs (fluphenazine, thioridazine, pimozide, or aripiprazole), we found that aripiprazole, administered at lower doses, had a much higher sensitization effect. We also demonstrated that co-treatment with another anti-mitotic drug (eribulin) increased the sensitization of KBV20C cells similar to VIC. We also found that aripiprazole had higher P-gp-inhibitory activity than the other bipolar drugs, indicating that this activity was involved in the higher level of VIC-aripiprazole sensitization. Conclusion: Co-treatment of anti-mitotic drug-resistant cancer cells with a low dose of aripiprazole had the strongest sensitization effect and is highly dependent on P-gp-inhibitory activity.
Hormone therapy targeting estrogen receptor α (ERα) is the most effective treatment for breast cancer. However, this treatment eventually fails as the tumor develops resistance. Although reduced expression of ER-α is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. The present study shows that Slug has an inverse relationship with ERα in breast and prostate cancer patient samples. Also the inhibition of Slug blocks mammary stem cell activity in primary mammary epithelial cells. We hypothesize that Slug may be a key transcription factor in the regulation of ERα expression. To understand the Slug-ERα signaling pathway, we employed resistant cell line MCF-TAMR (ERα relatively negative) derived from its parental MCF-7 (ERα positive) cell line and assessed changes in cell phenotype, activity and response to therapy. Conversely, we performed knockdown of Slug in the high-Slug expressing cell line MDA-MB-231 and assessed reversal of the mesenchymal phenotype. Microarray analysis showed that Slug is overexpressed in high grade breast and prostate cancer tissues. Additionally, Slug overexpression leads to drug resistance. Furthermore, we demonstrated that Slug binds directly to ERα promoter E-boxes and represses ERα expression. This resulted in decrease in epithelial-to-mesenchymal transition in cancer cells. These findings demonstrate that Slug, by regulation of ERα expression, contributes to tumor progression and could serve as an important target for cancer therapy.
BackgroudSmoking is a risk factor for cardiovascular diseases as well as pulmonary dysfunction. In particular, adolescent smoking has been reported to have a higher latent risk for cardiovascular disease. Despite the risk to and vulnerability of adolescents to smoking, the mechanisms underlying the effects of acute nicotine exposure on adolescents remain unknown. This study therefore evaluated the mechanism underlying the effects of linalyl acetate on cardiovascular changes in adolescent rats with acute nicotine exposure.MethodsParameters analyzed included heart rate (HR), systolic blood pressure, lactate dehydrogenase (LDH) activity, vascular contractility, and nitric oxide levels.ResultsCompared with nicotine alone, those treated with nicotine plus 10 mg/kg (p = 0.036) and 100 mg/kg (p = 0.023) linalyl acetate showed significant reductions in HR. Moreover, the addition of 1 mg/kg (p = 0.011), 10 mg/kg (p = 0.010), and 100 mg/kg (p = 0.011) linalyl acetate to nicotine resulted in significantly lower LDH activity. Nicotine also showed a slight relaxation effect, followed by a sustained recontraction phase, whereas nicotine plus linalyl acetate or nifedipine showed a constant relaxation effect on contraction of mouse aorta (p < 0.001). Furthermore, nicotine-induced increases in nitrite levels were decreased by treatment with linalyl acetate (p < 0.001).ConclusionsTaken together, our findings suggest that linalyl acetate treatment resulted in recovery of cell damage and cardiovascular changes caused by acute nicotine-induced cardiovascular disruption. Our evaluation of the influence of acute nicotine provides potential insights into the effects of environmental tobacco smoke and suggests linalyl acetate as an available mitigating agent.
Nocardia species are aerobic, gram-positive pathogens found worldwide in soil. Nocardia is considered an opportunistic pathogen, and its infection mostly occurs in immunocompromised patients. We report a case of Nocardia farcinica induced mediastinitis and pneumonia that occurred in a 64-year-old male patient who had no significant medical history except for hypertension. He visited another hospital with a complaint of dyspnea and left chest wall pain. The symptoms arose 7 days ago without any trauma and they worsened. A mediastinal mass was found on computed tomography scan. After being transferred to our hospital for further evaluation, he was diagnosed with mediastinitis and pneumonia. As N. farcinica was found to be the causative organism by 16S rRNA sequencing, proper antibiotic therapy including trimethoprim/sulfamethoxazole was initiated immediately. After this, the patient improved and he was discharged. If an infection has a disseminating course, nocardiosis cannot be excluded even in immunocompetent patients. Once the diagnosis is established, prompt antibiotic therapy should be performed based on the severity.
We report a case of agranulocytosis caused by ethambutol in a 79-year-old man with pulmonary tuberculosis. He was referred for fever and skin rash developed on 21th day after antituberculosis drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) intake. Complete blood count at the time of diagnosis of pulmonary tuberculosis was normal. On the seventh admission day, agranulocytosis was developed with absolute neutrophil count of 70/µL. We discontinued all antituberculosis drugs, and then treated with granulocyte colony-stimulating factor. Three days later, the number of white blood cell returned to normal. We administered isoniazid, pyrazinamide, and ethambutol in order with an interval. However, fever and skin rash developed again when adding ethambutol, so we discontinued ethambutol. After these symptoms disappeared, we added rifampicin and ethambutol in order with an interval. However after administering ethambutol, neutropenia developed, so we discontinued ethambutol again. He was cured with isoniazid, rifampicin, and pyrazinamide for 9 months.
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