Temozolomide combined with the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin inhibits melanoma cell growth, survival and invasion

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8559-8559 ◽  
Author(s):  
F. E. Meier ◽  
K. Lasithiotakis ◽  
B. Schittek ◽  
T. Sinnberg ◽  
C. Garbe
Keyword(s):  
Cell Growth ◽  
Metastatic Melanoma ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Mtor Inhibitor ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Pi3k Inhibitor ◽  
Mapk Signaling Pathways

8559 Background: Potential therapeutic targets in the treatment of metastatic melanoma have emerged, to which pharmacological inhibitors have been designed, which may enhance tumor chemosensitivity. In melanoma, dacarbazine is considered to be the most effective agent although total responses do not exceed 20% The clinical activity of temozolomide is similar to that of dacarbazine, but temozolomide has the advantages of being absorbed orally and of crossing the blood-brain barrier. Many clinical trials of targeted therapy and chemotherapy combinations lack rigorous preclinical evaluation and may neglect relevant mechanistic interactions. The PI3K-AKT-mTOR (AKT) and RAS-RAF- MEK-ERK (MAPK) signaling pathways are constitutively activated in melanoma, and appear to play a role in chemoresistance. Methods: In this study, a panel of pharmacological inhibitors was utilized in order to block the AKT and MAPK signaling pathways at different levels (AKT: PI3K, mTOR; MAPK: RAF, MEK) in 5 human metastatic melanoma cell lines. The effects on chemosensitivity to temozolomide and cisplatin was then investigated. Results: The effects of most inhibitors on chemosensitivity varied significantly between the different cell lines. However, LY294002, a PI3K inhibitor and rapamycin, an mTOR inhibitor, consistently enhanced chemosensitivity. Treatment of melanoma cells with temozolomide or cisplatin combined with LY294002 or rapamycin had a strong effect on melanoma cell growth and survival. Invasive melanoma growth in organotypic cultures of human skin was suppressed completely. The most pronounced potentiation of efficacy was seen with temozolomide in combination with rapamycin. Conclusions: These data suggest that LY294002 and rapamycin can render melanoma cells susceptible to apoptosis, induced by chemotherapeutic agents such as temozolomide and cisplatin. Since both temozolomide and rapamycin are used clinically, the combination of temozolomide with rapamycin might potentially be utilized as an approach in melanoma treatment. This combination merits clinical investigation. No significant financial relationships to disclose.

scholarly journals Vemurafenib resistant melanoma cells acquire mesenchymal stem cell-like properties

2019 ◽  
Vol 6 (4) ◽  
pp. 47-57
Author(s):  
A. A. Vartanian ◽  
O. S. Burova ◽  
Kh. S. Vishnyakova ◽  
I. V. Samoylenko ◽  
V. A. Misyurin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Acquired Resistance ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Brafv600e Mutation ◽  
Acquired Drug Resistance ◽  
Melanoma Patients ◽  
Braf Mutant ◽  
Melanoma Cell Lines

Background. Activating mutations in the BRAF gene leads to a constitutive activation of the MAPK signaling. The highly selective BRAFV600E inhibitor, vemurafenib, improves the overall survival of BRAF-mutant melanoma patients. However, despite the excellent results of response rate, the average duration of the response was short and acquired resistance develops in most BRAF mutated melanoma patients within a few months. Objective: to derive melanoma cell lines from surgical species of patients with BRAF mutant melanomas resistant to vemurafenib and to elucidate the mechanisms involved in acquired drug resistance.Materials and methods. Mel Ki and Mel F1702 melanoma cells were obtained from metastases of disseminated melanoma patients with BRAFV600E mutation. 2D tumor cell culture, MTT test, immunicytochemistry, flow cytometry, real-time polimerase chain reaction and osteogenic and adipocytic differentiation were used in the study.Results. We have derived two melanoma cell lines Mel Ki and Mel F1702 from tumor samples of patients with BRAFV600E mutation resistant to vemurafenib. These cells were homogenous and had fibroblastic morphology. The IC50 values for Mel Ki and Mel F1702 were 4.7 and 6.3 μM, respectively. The expression of cancer-testis antigens was not detected in both types of cells suggesting the stemness of Mel Ki and Mel F1702 melanoma cells. The immunophenotypic profile of the vemurafenib resistsant melanoma cells showed the expression of typical mesenchymal stem cells markers such as CD90, CD105 and CD44. In addition, we found that the melanoma cell lines derived from tumor resistant to vemurafenib differentiated into osteoblastand adipocyte-like cells. Conclusion. In this study we are offering an experimental evidence of the phenotypic transition of the vemurafenib-resistant melanoma cells into mesenchymal stem-like cells.

Down-regulation of NTSR3 inhibits cell growth and metastasis, as well as the PI3K–AKT and MAPK signaling pathways in colorectal cancer

2020 ◽  
Vol 98 (5) ◽  
pp. 548-555
Author(s):  
Aihua Liu ◽  
Zhongfu Zuo ◽  
Linlin Liu ◽  
Lihua Liu
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Signaling Pathways ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Mapk Signaling ◽  
Adhesion Assay ◽  
Caspase 9 ◽  
Down Regulation ◽  
Mapk Signaling Pathways

Colorectal cancer is a common malignancy. NTS receptor 3 (NTSR3) is known to play an important role in several cancers. This study examined the effects of NTSR3 on cell growth and metastasis in colorectal cancer. Western blot analysis, real-time PCR, immunofluorescence staining, MTT, cell cycle assay, cell apoptosis assay, Hoechst staining, caspase-3 and caspase-9 activity assays, cell adhesion assay, wound healing assay, and a Transwell assay were used in this study. We found that NTSR3 was expressed at relatively high levels in the colorectal cancer cell lines SW620 and SW480. NTSR3 knockdown suppressed cell growth and promoted cell apoptosis. Meanwhile, the protein expression levels of cyclinD1, cyclinE1, CDK4, and p-RB were reduced, and the levels of p-P27, P15, P21, cleaved caspase-3, and cleaved caspase-9 protein were increased. Cell invasiveness and cell migration were reduced with knockdown of NTSR3. In addition, our rescue experiments demonstrated that overexpression of the siRNA-resistant alleles of NTSR3 abrogated the NTSR3-siRNA-mediated effects on cell function. Further, down-regulation of NTSR3 inactivated the PI3K–AKT and MAPK signaling pathways. Collectively, these data demonstrate that knockdown of NTSR3 inhibits cell growth and metastasis, as well as the PI3K–AKT and MAPK signaling pathways in colorectal cancer. Thus, our results indicate that NTSR3 is a potential therapeutic target for treating colorectal cancer.

Impact of non-thermal plasma treatment on MAPK signaling pathways of human immune cell lines

Immunobiology ◽  
2013 ◽  
Vol 218 (10) ◽  
pp. 1248-1255 ◽  
Author(s):  
Lena Bundscherer ◽  
Kristian Wende ◽  
Katja Ottmüller ◽  
Annemarie Barton ◽  
Anke Schmidt ◽  
...  
Keyword(s):  
Plasma Treatment ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Thermal Plasma ◽  
Immune Cell ◽  
Mapk Signaling ◽  
Non Thermal Plasma ◽  
Human Immune ◽  
Mapk Signaling Pathways

scholarly journals Morin Induces Melanogenesis via Activation of MAPK Signaling Pathways in B16F10 Mouse Melanoma Cells

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2150
Author(s):  
SeoYeon Shin ◽  
JaeYeon Ko ◽  
MinJeong Kim ◽  
Nuri Song ◽  
KyungMok Park
Keyword(s):  
Protein Expression ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Tyrosinase Activity ◽  
Melanin Biosynthesis ◽  
Mouse Melanoma ◽  
Melanin Contents ◽  
Mapk Signaling Pathways

Morin is a well-known flavonoid, and has been reported to have various properties, such as anti-cell death, antioxidant, and anti-inflammatory properties. Although studies on the biochemical and biological actions of morin have been reported, the melanin biosynthesis effects and molecular mechanisms are unknown. In this study, we first found that morin has the effect of enhancing melanin biosynthesis in B16F10 mouse melanoma cells, and analyzed the molecular mechanism. In this study, we examined the effects of morin on the melanin contents and tyrosinase activity, as well as the protein expression levels of the melanogenic enzymes TRP-1, TRP-2, and microphtalmia-associated transcription factor (MITF) in B16F10 mouse melanoma cells. Morin showed no cytotoxicity in the concentration range of 5–100 μM, and significantly increased the intracellular tyrosinase activity and melanin contents. In mechanism analysis, morin increased the protein expression of TRP-1, TRP-2, and MITF associated with melanogenesis. Furthermore, morin increased phosphorylated ERK and p38 at the early time, and decreased phosphorylated ERK after 12 h. The results suggest that morin enhances melanin synthesis through the MAPK signaling pathways in B16F10 mouse melanoma cells.

scholarly journals E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis

2020 ◽  
Vol 295 (47) ◽  
pp. 16058-16071
Author(s):  
Valentina Montagnani ◽  
Luisa Maresca ◽  
Alessandro Apollo ◽  
Sara Pepe ◽  
Ryan M. Carr ◽  
...  
Keyword(s):  
Cell Growth ◽  
Malignant Melanoma ◽  
Melanoma Cell ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Braf V600e ◽  
Promising Therapeutic Approach ◽  
Melanoma Growth

Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence of BRAF/NRAS mutations and hyperactivation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), mitogen-activated protein kinases (MAPK), leading to uncontrolled melanoma growth. Efficacy of current targeted therapies against mutant BRAF or MEK1/2 have been hindered by existence of innate or development of acquired resistance. Therefore, a better understanding of the mechanisms controlled by MAPK pathway driving melanogenesis will help develop new treatment approaches targeting this oncogenic cascade. Here, we identify E3 ubiquitin ligase PARK2 as a direct target of ELK1, a known transcriptional effector of MAPK signaling in melanoma cells. We show that pharmacological inhibition of BRAF-V600E or ERK1/2 in melanoma cells increases PARK2 expression. PARK2 overexpression reduces melanoma cell growth in vitro and in vivo and induces apoptosis. Conversely, its genetic silencing increases melanoma cell proliferation and reduces cell death. Further, we demonstrate that ELK1 is required by the BRAF-ERK1/2 pathway to repress PARK2 expression and promoter activity in melanoma cells. Clinically, PARK2 is highly expressed in WT BRAF and NRAS melanomas, but it is expressed at low levels in melanomas carrying BRAF/NRAS mutations. Overall, our data provide new insights into the tumor suppressive role of PARK2 in malignant melanoma and uncover a novel mechanism for the negative regulation of PARK2 via the ERK1/2-ELK1 axis. These findings suggest that reactivation of PARK2 may be a promising therapeutic approach to counteract melanoma growth.

Effect of the farnesyl transferase inhibitor lonafarnib on sensitivity of melanoma cells to the multikinase inhibitor sorafenib and on Rheb farnesylation and mTOR signaling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9077-9077
Author(s):  
F. E. Meier ◽  
H. Niessner ◽  
K. Flaherty ◽  
D. Schadendorf ◽  
T. Sinnberg ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Chemotherapeutic Agents ◽  
Mtor Signaling ◽  
Akt Pathway ◽  
Multikinase Inhibitor ◽  
Farnesyl Transferase ◽  
Melanoma Cell Lines

9077 Background: Farnesyl transferase inhibitors (FTIs) inhibit the post-translational farnesylation of a number of target proteins, including Ras and Rheb, preventing their signaling function. Ras signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways which are constitutively activated in melanoma and appear to play a major role in tumor progression and drug resistance. Rheb positively regulates mTOR signaling. Methods: Using a panel of melanoma cell lines we evaluated the effects of the FTI lonafarnib alone and in combination with chemotherapeutic agents (temozolomide, cisplatin) or pharmacological MAPK pathway inhibitors (sorafenib, U0126, PD98059) or AKT pathway inhibitors (LY294002, wortmannin, rapamycin) on proliferation, survival and invasive tumor growth of melanoma cells in monolayer and organotypic culture. Results: Lonafarnib did not significantly inhibit growth of metastatic melanoma cells. Also, lonafarnib did not sensitize melanoma cells to the chemotherapeutic agents tested. Most combinations of the FTI lonafarnib with MAPK or AKT pathway inhibitors lacked significant enhancement of growth inhibition compared to monotherapy. In contrast, lonafarnib significantly augmented the growth inhibitory effects of the multikinase inhibitor sorafenib in eight metastatic melanoma cell lines tested. These effects did not appear to depend on BRAF or NRAS mutation status. Moreover, lonafarnib combined with sorafenib induced marked apoptosis and abrogated invasive melanoma growth. Interestingly, the FTI lonafarnib did not inhibit phosphorylation of ERK or AKT but of p70S6K, a downstream target of Rheb and mTOR signaling. Conclusions: These data suggest that lonafarnib sensitizes melanoma cells to sorafenib by inhibiting mTOR signaling via inhibition of Rheb farnesylation. No significant financial relationships to disclose.

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