Verapamil (VER) Enhances the Cytotoxic Effects of Docetaxel and Vinblastine Combined Therapy Against Non-Small Cell Lung Cancer Cell Lines

Drug Research ◽  
2017 ◽  
Vol 68 (03) ◽  
pp. 146-152 ◽  
Author(s):  
Soleiman Jaferian ◽  
Maryam Soleymaninejad ◽  
Hadis Daraee
Keyword(s):  
Lung Cancer ◽  
Combination Therapy ◽  
Combined Therapy ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Dapi Staining ◽  
Drug Induced ◽  
Glycoprotein P ◽  
Staining Result ◽  
Mdr 1

AbstractLung cancer is one of the foremost tumor-associated cause of death in the world. Most of the patients with NSCLC possesses an advanced disease at diagnosis, and are thus probable subject for systemic therapy. This study aims to evaluate the cytotoxicity of vinblastine and docetaxel combined therapy for the treatment of NSCLC, as well as verapamil (VER) enhancement of the combined therapy. We conducted P-glycoprotein (P-gp) gene expression, protein expression with RT-PCR and western blot respectively, apoptotic response of the combined therapy with VER is also determined using DAPI staining (%). Result of DAPI staining confirmed combination therapy promotes cell apoptosis to greater extent as compared to each drug alone. Real-time RT-PCR analysis revealed that mdr-1 expression level increased 6 fold with docetaxel (40 nM) and 2 fold with vinblastine (30 nM) after 24 h (p<0.001). Consequently, combination therapy reduced drug-induced up-regulation of mdr-1 significantly (p<0.05). VER with the drug combination increased P-gp expression (p<0.05). These data provide evidence showing combined therapy is a better approach to improve the efficacy of chemotherapy and decreasing drug resistance.

scholarly journals Histochemical Expression of Mast Cell Chymase in Chronic Periodontitis and Cyclosporine-Induced Gingival Overgrowth

2013 ◽  
Vol 2013 ◽  
pp. 1-5
Author(s):  
Tamilselvan Subramani ◽  
Kamatchiammal Senthilkumar ◽  
Soundararajan Periasamy
Keyword(s):  
Mast Cell ◽  
Chronic Periodontitis ◽  
Vital Role ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Drug Induced ◽  
Tissue Samples ◽  
Gingival Overgrowth ◽  
Significant Expression ◽  
Mast Cell Chymase

Mast cell (MC) mediators play a vital role in fibrosis. The purpose of this study was to investigate the MCs and their enzyme chymase in gingival tissues showing drug-induced gingival overgrowth (DIGO) and also to evaluate the correlation of MC counting and expression with the chronic periodontitis. In this study, 30 samples, including cyclosporine-induced gingival overgrowth, chronic periodontitis (10 for each), and ten normal gingival tissues, were collected. We analyzed the histochemical expression of MC chymase in all the collected tissues. In addition, the number of MCs was counted for each deparaffinized section stained with toluidine blue. Furthermore, total RNA was extracted from tissue samples, and RT-PCR was performed for MC chymase. The numbers of MCs were found to be increased in relative lesions compared to normal gingival tissues (). Moreover, chymase-containing MCs in DIGO tissues showed striking differences from those of control subjects and chronic periodontitis (). The RT-PCR analysis further revealed that MC chymase mRNA increased significantly in DIGO tissues. In conclusion, although the MCs were less numerous in numbers, the cells exhibited significant expression of chymase enzyme suggesting the involvement of MCs in DIGO.

Abstract 2966: Role of the Cerebral Vascular Toll-Like Receptor Signaling Pathway in Neuroprotection Induced by Combination Therapy of VELCADE and TPA

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Li Zhang ◽  
Zheng Gang Zhang ◽  
Hua Teng ◽  
Xianshuang Liu ◽  
Michael Chopp
Keyword(s):  
Endothelial Cells ◽  
Combination Therapy ◽  
Signaling Pathway ◽  
Cell Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Western Blots ◽  
Cerebral Endothelial Cells

Background and Purpose: Toll-like receptors (TLRs) and their family members including IL-1 receptor-associated kinase-1 (IRAK1) mediate ischemic cell damage. MicroRNAs (miRNAs) including miR-146a regulate TLRs. The present study investigated whether treatment of stroke in older animals with VELCADE in combination with tPA affects expression of TLRs and miR-146a in cerebral endothelial cells. Methods: Wistar rats at the age of 16-18 months were subjected to right embolic middle cerebral artery occlusion (MCAo). VELCADE (0.1mg/kg) and tPA (5mg/kg) were intravenously administered 2h after MCAo (n=16). Ischemic rats treated with tPA alone (n=14) or saline (n=15) were used as control groups. Levels of TLRs and miR-146a in cerebral endothelial cells were measured. Cultured primary cerebral endothelial cells (PCECs) were used for investigating the direct effect of VELCADE on expression of miR-146a. Results: Quantitative RT-PCR analysis revealed that VELCADE in combination with tPA significantly increased miR-l46a levels (11±3 fold) in the cerebral endothelial cells isolated by laser capture microdissection compared with that in ischemic rats treated with tPA monotherapy (2±1). Concurrently, immunostaining showed that the combination therapy suppressed tPA monotherapy-upregulated TLR2 (44±7 vs 93±8/mm 2 in tPA), TLR4 (39±6vs 91±8), IRAK1 (16±3 vs 46±5), fibrin (17±6 vs 40±3), and NF-kB (9±2 vs 22±3) immunoreactive vessels, leading to reduction of infarct volume (14±2 vs 28±3% in tPA, and 30±3% in saline, p<0.05). These in vivo data indicate that combination therapy-upregulated miR-146a is inversely related with TLRs levels and ischemic cell damage. In vitro, Western blots showed that incubation of PCECs with fibrin at 1.5 µg/ml increased levels of IRAK1 (1.4 fold) and myeloid differentiation factor 88 (MyD88, 1.4 fold). RT-PCR analysis of PCECs showed that fibrin reduced miR-146a levels by 30 %. However, PCECs treated with VELCADE (10 ng/ml) in the presence of fibrin elevated miR-146 levels by 80% and abolished fibrin-elevated IRAK1 and MyD88 proteins. Moreover, overexpression of miR146a in PCECs downregulated IRAK1 protein, a miR-146a target, by 40%. Conclusion: Our data demonstrate that fibrin activates endothelial TLRs and that VELCADE-upregulated miR-146a abolishes tPA-induced TLRs, suggesting that miRNAs and the TLR signaling pathway in cerebral endothelial cells play an important role in the neuroprotective effect of the combination therapy of VELCADE and tPA for acute stroke.

A phase I trial of intravenous therapy with tumor suppressor FUS1-nanoparticles for recurrent/metastatic lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19065-e19065 ◽  
Author(s):  
C. Lu ◽  
D. J. Stewart ◽  
L. Ji ◽  
R. Ramesh ◽  
G. Jayachandran ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Local Treatment ◽  
Pcr Analysis ◽  
Metastatic Lung Cancer ◽  
Rt Pcr ◽  
Platinum Based Chemotherapy ◽  
Metastatic Lung ◽  
Tumor Biopsies

e19065 Background: The tumor suppressor gene FUS1 is frequently inactivated early in lung cancer development. FUS1 mediates apoptosis in cancer cells but not normal cells through its interaction with Apaf1. DOTAP:cholesterol nanoparticles encapsulating a FUS1 expression plasmid showed selective uptake by cancer cells and activity in mouse xenograft metastatic lung cancer models. Methods: Patients with recurrent/metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous DOTAP:cholesterol FUS1 nanoparticles. Nanoparticle-DNA complexes were manufactured in GMP facilities to meet specifications of OD400, size, appearance, and transfection efficiency. Results: Patients have received doses ranging from 0.01–0.09 mg/kg at 3 week intervals. To date 23 patients have been entered on study at 6 dose levels, with 21 patients currently evaluable for the primary endpoint of cycle 1 toxicity. 70% of subjects had received 2 or more prior chemotherapy regimens. Among 4 patients treated without premedications, all 4 developed grade 2 or higher fevers within 24 hours of treatment. Among the 17 patients premedicated with dexamethasone and diphenhydramine, 4 developed grade 1 fever. There have been no other grade 2 or higher drug-related toxicities. Four patients received only one dose because of rapidly progressing disease at a site requiring local treatment. Fifteen patients received two or more doses and are evaluable for response, with 4 patients achieving stable disease and 11 patients progressing. Median survival time for all patients is 10.3 months. A maximum tolerated dose (MTD) has not been reached. Pre and 24 hour posttreatment tumor biopsies were obtained from 4 patients. A quantitative real time reverse transcriptase PCR (RT-PCR) analysis using a plasmid FUS1 sequence-specific probe have been performed on 3 paired-samples blinded to time of biopsy. A high level of plasmid FUS1 expression was detected in all 3 posttreatment samples but not in three pretreatment samples and negative controls by RT-PCR. Conclusions: DOTAP:cholesterol FUS1 nanoparticles can be safely administered intravenously in lung cancer patients with demonstrable gene expression in posttreatement tumor biopsies. [Table: see text]

Quantitative RT-PCR analysis and immunohistochemical localization of the kallikrein-related peptidases 13 and 14 in lung

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Chris Planque ◽  
Claire Bléchet ◽  
Aida Ayadi-Kaddour ◽  
Nathalie Heuzé-Vourc'h ◽  
Pascal Dumont ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immunohistochemical Localization ◽  
Small Cell ◽  
Pcr Analysis ◽  
Positive Staining ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Small Cell Lung ◽  
Protein Levels ◽  
Positive Nodal Status

Abstract Expression of the KLK13 and KLK14 genes was examined at the mRNA and protein levels in a cohort of 57 patients with non-small-cell lung cancer (NSCLC). The mRNA levels, assessed by real-time RT-PCR, were significantly different in malignant tissues compared to adjacent non-malignant tissues (KLK13, p=0.006; KLK14, p=0.022). KLK13 and KLK14 mRNA overexpression in tumors (1/3 of the patients) was associated with a positive nodal status in multivariate analysis (p=0.018 and p=0.069, respectively). KLK13 and KLK14 were localized in the cytoplasm of epithelial cells of normal bronchus and NSCLC, as determined by immunohistochemistry. Moreover, positive staining was significantly associated with adenocarcinoma histotype (KLK13, p=0.014) and tumor size (KLK14, p=0.048). Although the results are marginally significant, patients with high KLK13 expression at the mRNA or protein level had lower overall survival.

DETECTION OF RESIDUAL LUNG CANCER CELLS BY PCR-BASED GENETIC TESTING FOR ROS1-TRANSLOCATION: CASE REPORT

2018 ◽  
Vol 64 (3) ◽  
pp. 331-334
Author(s):  
Fedor Moiseenko ◽  
Vladislav Tyurin ◽  
Nikita Levchenko ◽  
Yevgeniy Levchenko ◽  
Aglaya Ievleva ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Morphological Analysis ◽  
Pathologic Complete Response ◽  
Residual Tumor ◽  
Complete Response ◽  
Convincing Evidence ◽  
Pcr Analysis ◽  
Specific Gene ◽  
Highly Sensitive ◽  
Reliable Monitoring

A patient with lung cancer carrying ROS1 translocation was treated by crizotinib and then subjected to surgery. Morphological analysis revealed pathologic complete response in surgically removed tissues, while PCR test provided convincing evidence for the presence of residual tumor cells. PCR analysis of lung cancer specific gene translocations allows carrying out highly sensitive and reliable monitoring of tumor disease during the course of treatment.

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

2019 ◽  
Vol 19 (23) ◽  
pp. 2128-2142 ◽  
Author(s):  
Hao He ◽  
Chang Xu ◽  
Zhao Cheng ◽  
Xiaoying Qian ◽  
Lei Zheng
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Egfr Tki ◽  
Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

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