scholarly journals Depletion of Endogenous Nitric Oxide Enhances Cisplatin-induced Apoptosis in ap53-dependent Manner in Melanoma Cell Lines

2003 ◽  
Vol 279 (1) ◽  
pp. 288-298 ◽  
Author(s):  
Chi-Hui Tang ◽  
Elizabeth A. Grimm
Keyword(s):  
Nitric Oxide ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Dependent Manner ◽  
Endogenous Nitric Oxide ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

Effect of small inhibitors of nuclear export (SINE) on growth inhibition and apoptosis of human melanoma cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13549-e13549
Author(s):  
Gregory B. Lesinski ◽  
Jennifer Yang ◽  
Matthew A Bill ◽  
Yosef Landesman ◽  
Sharon Shacham ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Nuclear Export ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Melanoma Cell Lines

e13549 Background: Inhibition of nuclear export can promote re-activation of tumor suppressor pathways. CRM1 (chromosomal regional maintenance 1) or XPO1 (exportin 1) is the major protein that mediates nuclear export. We hypothesized that CRM1 mediated nuclear export represents a novel therapeutic target that can be manipulated to inhibit melanoma cell survival. Methods: The growth inhibitory and pro-apoptotic effects of KPT-185, KPT-276 and KPT-330, small molecules selective inhibitor of nuclear export (SINE) were evaluated in human melanoma cell lines using an MTT assay and Annexin V/PI staining, respectively. Fluorescence microscopy and immunoblots were used to assess nuclear accumulation of tumor suppressor proteins. The trans-isomer of KPT-185 and DMSO (vehicle) were used as a negative controls in all assays. The pharmacokinetic (PK) profile of all compounds was evaluated in mice. Results: CRM1 protein was highly expressed in human melanoma cell lines with diverse molecular profiles (i.e., B-Raf, NRAS, p53). KPT-SINE inhibited melanoma cell growth in a concentration-dependent manner and induced apoptosis at nanomolar concentrations. Importantly, there was no evidence that B-Raf V600 mutational status influenced melanoma cell response to these agents. Nuclear accumulation and/or induction of p53, p21, FOXO3a, STAT1 and BAD, and reduction of MCL-1 occurred in melanoma cells at time points prior to apoptosis as shown by increase in cleaved PARP and caspase 3 levels. PK studies were conducted in mice following oral administration of 10 mg/kg, to guide drug selection for our ongoing efficacy studies in murine melanoma models. KPT-185 showed limited bioavailability and systemic exposure, while KPT-276 and KPT-330 showed >50% bioavailability reaching Cmax >5µM. Conclusions: This study represents the first report of CRM1 inhibition in melanoma. These data indicate that the novel SINE compounds can effectively inhibit CRM1-mediated nuclear export and induce apoptosis in melanoma cells. KPT-330 is currently under development as orally bioavailable, small molecule inhibitors for a human clinical trial.

scholarly journals Induction of matrix metalloproteinase gene transcription by nitric oxide and mechanisms of MMP-1 gene induction in human melanoma cell lines

2002 ◽  
Vol 103 (2) ◽  
pp. 161-168 ◽  
Author(s):  
Yoshiyuki Ishii ◽  
Tsutomu Ogura ◽  
Masayuki Tatemichi ◽  
Hiroshi Fujisawa ◽  
Fujio Otsuka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Matrix Metalloproteinase ◽  
Cell Lines ◽  
Gene Transcription ◽  
Melanoma Cell ◽  
Gene Induction ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Melanoma Cell Lines

scholarly journals GSK-3β Inhibition Enhances Sorafenib-induced Apoptosis in Melanoma Cell Lines

2007 ◽  
Vol 283 (2) ◽  
pp. 726-732 ◽  
Author(s):  
David J. Panka ◽  
Daniel C. Cho ◽  
Michael B. Atkins ◽  
James W. Mier
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Gsk 3Β ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

BIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines

2017 ◽  
Vol 404 ◽  
pp. 70-78 ◽  
Author(s):  
Andreas Borst ◽  
Sebastian Haferkamp ◽  
Johannes Grimm ◽  
Manuel Rösch ◽  
Guannan Zhu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Mek Inhibitor ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

Prothrombin and Its Derivatives Stimulate Motility of Melanoma Cells

1998 ◽  
Vol 80 (09) ◽  
pp. 407-412 ◽  
Author(s):  
Hong Zhou ◽  
Esteban Gabazza ◽  
Hiroyuki Takeya ◽  
Hiroshi Deguchi ◽  
Hajime Urano ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Chemotactic Activity ◽  
Dependent Manner ◽  
Binding Assays ◽  
Clotting Factors ◽  
Clotting System ◽  
Concentration Dependent Manner ◽  
Melanoma Cell Lines

SummarySeveral studies indicated that activation of the clotting system may promote the growth and the invasive behavior of tumor cells. In the present study, we evaluated the migratory response of various melanoma cell lines to several clotting factors and prothrombin derivatives (thrombin, fragment 1, fragment 2 and kringle 1 fragment). Prothrombin, thrombin and fragment 1 stimulated chemotaxis of the murine (K-1735 M2, X21) and human A375 (SM) melanoma cell lines. Prothrombin and prothrombin fragment 1 showed their maximal chemo-tactic activity at 0.5~1 μM. Chemotaxis induced by thrombin was inhibited by hirudin, but not that induced by prothrombin or fragment 1. Other clotting proteins and the fragment 2 and kringle 1 fragment of prothrombin did not elicit chemotactic activity. Checkerboard analysis indicated that motility was directional with a significant chemokinetic component. The K-1735 M2 cells also migrated in a concentration-dependent manner to substratum-bound insoluble prothrombin, thrombin or fragment 1. Ligand binding assays showed that both prothrombin and fragment 1 bound to K-1735 M2 cells with apparent Kds of 0.5 μM. This binding was inhibited by an excess concentration of unlabeled prothrombin and fragment 1 but not by similar concentrations of other prothrombin fragments. These findings suggest that prothrombin and its fragment 1 exert chemotactic activity on melanoma cells by different mechanisms and different binding sites from that induced by thrombin.

scholarly journals Investigating the Effects of Shikonin, Deoxyshikonin, and (β,β-Dimethylacryl)Shikonin on Melanoma Cell Lines

2020 ◽  
Vol 15 (4) ◽  
pp. 1934578X2092232
Author(s):  
Jin Jie Dillon Ng ◽  
Zee Upton ◽  
David Leavesley ◽  
Chen Fan
Keyword(s):  
Cell Migration ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Mitogen Activated Protein Kinase ◽  
High Rate ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

Melanoma is the most lethal form of various skin cancers and contributes to more than 79% of all skin cancer deaths. Although there are numerous therapies available for melanoma, the high rate of recurrence in melanoma post-therapy remains a challenging issue for both patients and clinicians. Apoptosis is one of the foundations for cancer treatment as deficient apoptosis is one of the most essential reasons for the formation of tumour tissues. Shikonin (SHI), an active component extracted from Lithospermum erythrorhizon, has been broadly demonstrated to possess antitumorigenic property due to its apoptosis-inducing ability in various cancer cell lines. The analogs of SHI, such as deoxyshikonin (DO-SHI) and (β,β-dimethylacryl)shikonin (β,β-SHI), have also been found to possess similar bioactivities. The apoptosis-inducing ability of SHI and its analogs enable them to be potential anticancer therapies. In this study reported herein, we investigated the effects of SHI, DO-SHI, and β,β-SHI on both human (A375) and mouse (B16-F0 and B16-F10) melanoma cell lines. Cell viability was measured using Alamar blue assay, while cell migration was detected using scratch assay. Cell apoptosis was captured using terminal deoxynucleotidyl dUTP nick end labeling and fluorescence activated cell sorting. Signaling pathway activation was detected using Western blotting. Our results revealed that SHI, DO-SHI, and β,β-SHI reduce cell viability, inhibit cell migration, and induce apoptosis in melanoma cell lines. These 3 molecules-induced apoptosis in A375 is regulated via mitogen-activated protein kinase/caspase 3 signaling pathway. In particular, DO-SHI and β,β-SHI induce higher apoptosis rate in A375 and B16-F0 compared to SHI. The data from this study demonstrate that DO-SHI and β,β-SHI offer potential new reagents for managing melanoma.

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