scholarly journals EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAFV600E Mutated Parent- and Vemurafenib-Resistant Melanoma

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 504 ◽  
Author(s):  
Yige Fu ◽  
Drishti Rathod ◽  
Ehab Abo-Ali ◽  
Vikas Dukhande ◽  
Ketan Patel
Keyword(s):  
Lipid Bilayers ◽  
Cell Lines ◽  
Mek Inhibitor ◽  
Parental Cell ◽  
Resistant Cell ◽  
Mitogen Activated Protein Kinase ◽  
Hydrodynamic Diameter ◽  
Burst Release ◽  
Scanning Calorimetry ◽  
Mitogen Activated Protein

The clinical outcomes of malignant melanoma have improved with the introduction of mitogen-activated protein kinase kinase (MEK) inhibitors. However, off-target toxicities of the MEK inhibitor trametinib (TMB) often result in dose interruption and discontinuation of therapy. The purpose of this study was to anchor a physically stable EphrinA1-mimicking peptide known as YSA (YSAYPDSVPMMS) on TMB-loaded PEGylated nanoliposomes (YTPLs), and evaluate them in BRAFV600E-mutated parent cells (lines A375 and SK-MEL-28) and vemurafenib-resistant cells lines (A375R and SK-MEL-28R) in melanoma. TMB-loaded PEGylated liposomes (TPL) functionalized with nickel-chelated phospholipids were prepared using a modified hydration method. The hydrodynamic diameter and zeta potential values of optimized YTPL were 91.20 ± 12.16 nm and –0.92 ± 3.27 mV, respectively. The drug release study showed TPL did not leak or burst release in 24 h. The hemolysis observed was negligible at therapeutic concentrations of TMB. A differential scanning calorimetry (DSC) study confirmed that TMB was retained in a solubilized state within lipid bilayers. YTPL showed higher intracellular uptake in parental cell lines compared to vemurafenib-resistant cell lines. Western blot analysis and a cytotoxicity study with the EphA2 inhibitor confirmed a reduction in EphA2 expression in resistant cell lines. Thus, EphA2 receptor-targeted nanoliposomes can be useful for metastatic melanoma-specific delivery of TMB.

Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines

1992 ◽  
Vol 12 (9) ◽  
pp. 3689-3698
Author(s):  
W Zhen ◽  
C J Link ◽  
P M O'Connor ◽  
E Reed ◽  
R Parker ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ovarian Cancer Cell ◽  
Parental Cell ◽  
Resistant Cell ◽  
Dhfr Gene ◽  
Human Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Lines ◽  
Repair Efficiency ◽  
Interstrand Cross Links ◽  
Cross Links

We have studied several aspects of DNA damage formation and repair in human ovarian cancer cell lines which have become resistant to cisplatin through continued exposure to the anticancer drug. The resistant cell lines A2780/cp70 and 2008/c13*5.25 were compared with their respective parental cell lines, A2780 and 2008. Cells in culture were treated with cisplatin, and the two main DNA lesions formed, intrastrand adducts and interstrand cross-links, were quantitated before and after repair incubation. This quantitation was done for total genomic lesions and at the level of individual genes. In the overall genome, the initial frequency of both cisplatin lesions assayed was higher in the parental than in the derivative resistant cell lines. Nonetheless, the total genomic repair of each of these lesions was not increased in the resistant cells. These differences in initial lesion frequency between parental and resistant cell lines were not observed at the gene level. Resistant and parental cells had similar initial frequencies of intrastrand adducts and interstrand cross-links in the dihydrofolate reductase (DHFR) gene and in several other genes after cisplatin treatment of the cells. There was no increase in the repair efficiency of intrastrand adducts in the DHFR gene in resistant cell lines compared with the parental partners. However, a marked and consistent repair difference between parental and resistant cells was observed for the gene-specific repair of cisplatin interstrand cross-links. DNA interstrand cross-links were removed from three genes, the DHFR, multidrug resistance (MDR1), and delta-globin genes, much more efficiently in the resistant cell lines than in the parental cell lines. Our findings suggest that acquired cellular resistance to cisplatin may be associated with increased gene-specific DNA repair efficiency of a specific lesion, the interstrand cross-link.

scholarly journals Role of Mitogen-Activated Protein Kinase Pathway in Prostaglandin F2α-Induced Rat Puerperal Uterine Contraction

Endocrinology ◽  
1997 ◽  
Vol 138 (8) ◽  
pp. 3103-3111 ◽  
Author(s):  
Masahide Ohmichi ◽  
Koji Koike ◽  
Akiko Kimura ◽  
Kanji Masuhara ◽  
Hiromasa Ikegami ◽  
...  
Keyword(s):  
Map Kinase ◽  
Uterine Contraction ◽  
Prostaglandin F2α ◽  
Mek Inhibitor ◽  
Biological Action ◽  
Mitogen Activated Protein Kinase ◽  
Myometrial Cells ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

Abstract In this study, prostaglandin (PG) F2α was found to activate mitogen-activated protein (MAP) kinase and MAP kinase kinase (MEK) in cultured rat puerperal uterine myometrial cells. PGF2α stimulation also led to an increase in phosphorylation of raf-1, son of sevenless (SOS), and Shc. Furthermore, we examined the mechanism by which PGF2α induced MAP kinase phosphorylation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the β-adrenergic receptor kinase 1 (βARK1), which specifically blocks signaling mediated by the βγ subunits of G proteins, blocked the PGF2α-induced activation of MAP kinase. Ritodrine (1 μm), which is known to relax uterine muscle contraction, attenuated PGF2α-induced tyrosine phosphorylation of MAP kinase. Moreover, to examine the role of MAP kinase pathway in uterine contraction, an inhibitor of MEK activity, PD098059, was used. Although MEK inhibitor had no effect on PGF2α-induced calcium mobilization, this inhibitor partially inhibited PGF2α-induced uterine contraction. These results provide evidence that PGF2α stimulates the MAP kinase signaling pathway in cultured rat puerperal uterine myometrial cells through Gβγ protein, suggesting that this new pathway may play an important role in the biological action of PGF2α on these cells.

Clinical efficacy with dabrafenib and trametinib in a T599_V600insT poorly differentiated metastatic thyroid carcinoma

2021 ◽  
Vol 14 (8) ◽  
pp. e243264
Author(s):  
Chung-Shien Lee ◽  
Emily Miao ◽  
Kasturi Das ◽  
Nagashree Seetharamu
Keyword(s):  
Thyroid Carcinoma ◽  
Kinase Inhibitors ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Effective Treatment Option ◽  
Mitogen Activated Protein ◽  
Treatment Data ◽  
Poorly Differentiated

BRAF (v-raf murine sarcoma viral oncogene homolog B1) and MEK (mitogen-activated protein kinase kinase) inhibitors have been shown to improve clinical outcomes in tumours presenting with mutations in the BRAF gene. The most common form of BRAF mutation is V600E/K and has been shown to occur in thyroid cancers. Treatment data for patients harbouring less frequent BRAF mutations are limited. In vitro studies have shown that mutations in codons 599–601 increase kinase activity similar to that in V600E mutations, which suggests that BRAF and MEK inhibitors could be an effective treatment option. Here, we report a case of a patient with thyroid carcinoma harbouring a rare amino acid insertion in codon 599 of the BRAF gene (T599_V600insT) treated with a BRAF and MEK inhibitor.

Analysis of mRNAs and ncRNAs and Prediction Competing Endogenous RNA Networks in Colorectal Cancer Chemo-Resistance by Whole-Transcriptome Sequencing

2020 ◽  
Author(s):  
Fei Yao ◽  
Chuanren Zhou ◽  
Qiyou Huang ◽  
Xiaoying Huang ◽  
Jie Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Transcriptome Sequencing ◽  
Regulatory Networks ◽  
Parental Cell ◽  
Resistant Cell ◽  
Competing Endogenous Rna ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

Abstract Background: Chemo-resistance is a major clinical obstacle to the treatment of colorectal cancer (CRC), mRNAs and non-coding RNAs (ncRNAs) have been reported to modulate the development of chemo-resistance. However, the profiles of mRNAs and ncRNAs as well as competing endogenous RNA (ceRNA) networks in CRC chemo-resistance are still unclear, and whether different drug resistance of CRC have the same mechanisms also needs to be explored. This study aims to uncover the expression of mRNAs and ncRNAs in parental cell lines and different chemo-resistant cell lines, and construct ceRNA regulatory networks by whole-transcriptome sequencing.Methods: The expression of mRNAs and ncRNAs in parental cell lines and drug-resistant cell lines were identified by whole-transcriptome sequencing and bioinformatics methods.Results: A total of 1779 mRNAs, 64 miRNAs, 11 circRNAs and 295 lncRNAs were common differentially expressed in two different chemo-resistant cell lines when compared with the control. In addition, 5,767 lncRNA-miRNA-mRNA relationship pairs and 47 circRNA-miRNA-mRNA pathways were constructed according to ceRNA regulatory rules, in which AC109322.2-hsa-miR-371a-5p-BTNL3 and hsacirc_027876-hsa-miR-582-3p-FREM1 were identified as the most potential ceRNA networks involved in drug resistance to CRC. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of two ceRNA regulatory networks showed that the TNF signaling pathway may be crucial in the process of CRC drug resistance.Conclusions: A large number of mRNAs and ncRNAs in chemo-resistant cell lines were different expressed, which may play pivotal roles in development of drug resistance through the ceRNA regulatory network. This study may improve our understanding of the underlying mechanisms and provide a promising therapeutic strategy for CRC chemo-resistance.

scholarly journals MicroRNA-132 Plays an Independent Prognostic Role in Pancreatic Ductal Adenocarcinoma and Acts as a Tumor Suppressor

2019 ◽  
Vol 18 ◽  
pp. 153303381882431 ◽  
Author(s):  
Yan Chen ◽  
Huiyun Zhu ◽  
Yuqiong Wang ◽  
Yingxiao Song ◽  
Pingping Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Prognostic Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Adenocarcinoma Cell ◽  
Nuclear Transcription Factor ◽  
Mitogen Activated Protein

The role of microRNA-132 in human pancreatic ductal adenocarcinomas is still ambiguous. We explored the association between microRNA-132 and pancreatic ductal adenocarcinoma prognosis. The expression of microRNA-132 in 50 pancreatic ductal adenocarcinoma tissue samples and pancreatic ductal adenocarcinoma cell lines was examined, and the association between its expression and pancreatic ductal adenocarcinoma prognosis was assessed. Functional analysis and factors downstream of microRNA-132 were investigated. Kaplan-Meier survival curves showed that high expression of microRNA-132 was a significant prognostic factor for 1-year survival of patients with pancreatic ductal adenocarcinoma ( P = .028). Multivariate analysis for overall survival indicated that high expression of microRNA-132 was an independent prognostic factor for patients with pancreatic ductal adenocarcinoma ( P = .044). Low expression of microRNA-132 was associated with poor prognosis in pancreatic ductal adenocarcinoma. Ectopic expression of microRNA-132 significantly inhibited proliferation and promoted apoptosis of 2 pancreatic ductal adenocarcinoma cell lines. Bioinformatic analysis revealed that microRNA-132 may exert its effects on pancreatic ductal adenocarcinoma through downregulating mitogen-activated protein kinase 3 and nuclear transcription factor Y subunit α. The results of this study further our understanding of the relationship between microRNA-132 and pancreatic ductal adenocarcinoma by showing that microRNA-132 might inhibit the progression of pancreatic ductal adenocarcinoma by regulating mitogen-activated protein kinase and nuclear transcription factor Y subunit alpha.

scholarly journals Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

2020 ◽  
Vol 21 (6) ◽  
pp. 2167
Author(s):  
Jingxuan Zhu ◽  
Congcong Li ◽  
Hengzheng Yang ◽  
Xiaoqing Guo ◽  
Tianci Huang ◽  
...  
Keyword(s):  
Molecular Dynamic ◽  
Conformational Changes ◽  
Computational Study ◽  
Md Simulations ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Lung Cancers ◽  
Mitogen Activated Protein ◽  
Alk Positive

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

scholarly journals Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Jun-Ying Wang ◽  
Renbo Chen ◽  
Shu-Ping Chen ◽  
Yong-Hui Gao ◽  
Jian-Liang Zhang ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Electrical Activity ◽  
Nerve Stimulation ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Noxious Stimulation ◽  
Ca1 Region ◽  
Mitogen Activated Protein ◽  
Hippocampal Area ◽  
Sciatic Nerve Stimulation

To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA) and mitogen-activated protein kinase (MEK) inhibitor on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal area CA1 of sham or chronic constrictive injury (CCI) rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor) group. In all experiments, we briefly (10-second duration) stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase) signaling pathway is involved in the modulation of EA analgesia.

Mitogen-activated protein kinase mediation of hemolysate-induced contraction in rabbit basilar artery

1999 ◽  
Vol 90 (6) ◽  
pp. 1091-1097 ◽  
Author(s):  
Alexander Y. Zubkov ◽  
Kotaro Ogihara ◽  
Phani Tumu ◽  
Anita Patlolla ◽  
Adam I. Lewis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Basilar Artery ◽  
Kinase Inhibitor ◽  
Contractile Response ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Western Blots ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Fine Print

Object. Mitogen-activated protein kinase (MAPK) is an important signaling factor in vascular proliferation and contraction, which are the two features of cerebral vasospasm that follow subarachnoid hemorrhage. The authors studied the possible involvement of MAPK in hemolysate-induced signal transduction and contraction in rabbit basilar artery (BA).Methods. Isometric tension was used to record the contractile response of rabbit BA to hemolysate, and Western blots were obtained using antibodies for MAPK.The following results are reported. 1) Hemolysate produced a concentration-dependent contraction of rabbit BA; however, preincubation of arteries with the MAPK kinase (MEK) inhibitor PD-98059 markedly reduced this contraction. The administration of PD-98059 also relaxed, in a concentration-dependent fashion, the sustained contraction induced by 10% hemolysate. 2) The Janus tyrosine kinase 2 inhibitor AG-490, preincubated with arterial rings, reduced the contractile response to hemolysate but failed to relax the sustained contraction induced by this agent. The Src-tyrosine kinase inhibitor damnacanthal and the phosphatidylinositol 3—kinase inhibitor wortmannin failed to reduce hemolysate-induced contraction. 3) Hemolysate produced a time-dependent elevation of MAPK immunoreactivity as seen on Western blots of rabbit BA. The MAPK was enhanced 1 minute after hemolysate exposure and the effect reached maximum levels at 5 minutes. The immunoreactivity of MAPK decayed slowly over time, but the level of this kinase was still higher than the basal level, even at 2 hours after exposure to hemolysate. Preincubation of arteries with the MEK inhibitor PD-98059 abolished the effect of hemolysate on MAPK immunoreactivity.Conclusions. Hemolysate produced contraction of rabbit BA, possibly by activation of MAPK, and therefore MAPK inhibitors may be useful in the treatment of cerebral vasospasm.

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