A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib

Graziani, Grazia; Artuso, Simona; Luca, Anastasia De; Muzi, Alessia; Rotili, Dante; Scimeca, Manuel; Atzori, Maria Grazia; Ceci, Claudia; Mai, Antonello; Leonetti, Carlo; Levati, Lauretta; Bonanno, Elena; Tentori, Lucio; Caccuri, Anna Maria

doi:10.1016/j.bcp.2015.03.004

Cited by 30 publications

(35 citation statements)

References 41 publications

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“…Of note, when WM266.4 cells were treated with higher MC3181 concentrations (i.e. 2.0 and 4.0 μM) we observed a persistent JNK activation that paralleled an increase of apoptotic cells, as previously reported (Supplementary Figure 6) [5, 6]. Phospho-activation of p38 was also significantly affected by 1.0 μM MC3181 up to 48 hours (P-p38, Figure 7c).…”

Section: Resultssupporting

confidence: 85%

“…In contrast with current clinical trials targeting multiple signaling pathways involved in cell proliferation, we recently reported that the nitrobenzoxadiazole derivatives (NBDs) NBDHEX [6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol] and its more water-soluble analogue, MC3181 [2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol], exert a potent antitumor activity through the activation of different MAPK pathways. These compounds represent a new class of antitumor agents exhibiting an outstanding therapeutic activity together with an extremely non-toxic profile in human cutaneous melanoma mouse xenografts.…”

Section: Introductionmentioning

confidence: 99%

“…NBDHEX and MC3181 inhibit glutathione transferase P1-1 (GSTP1-1), and disrupt the GSTP1-1/JNK1 and GSTP1-1/TRAF2 complexes, thereby causing prolonged tumor cell cycle arrest and apoptosis. Therefore, these drugs may constitute a new effective strategy for the treatment of BRAF-mutated human melanomas, capable of overcoming the resistance to vemurafenib [5, 6]. …”

Section: Introductionmentioning

confidence: 99%

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The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

et al. 2017

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The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenib-resistant human melanoma xenografts. Here, we report that subtoxic concentrations of this compound significantly reduced invasiveness of BRAF-V600D mutated WM115 and WM266.4 melanoma cell lines derived from the primary lesion and related skin metastasis of the same patient, respectively. The strong antimetastatic activity of MC3181 was observed in both 2D monolayer cultures and 3D multicellular tumor spheroids, and confirmed in vivo by the significant decrease in the number of B16-F10 melanoma lung metastases in drug-treated mice. Our data also show that MC3181 affects the lactate production in the high glycolytic WM266.4 cell line. To unveil the MC3181 mechanism of action, we analyzed the ability of MC3181 to affect the degree of activation of different MAPK pathways, as well as the expression/activity levels of several proteins involved in angiogenesis, invasion, and survival (i.e. AP2, MCAM/MUC18, N-cadherin, VEGF and MMP-2). Our data disclosed both a decrease of the phospho-active form of JNK and an increased expression of the transcription factor AP2, events that occur in the very early phase of drug treatment and may be responsible of the antimetastatic effects of MC3181.

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Section: Resultssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

et al. 2017

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“…After 7–10 days of culture, colonies were fixed, stained with 0.5% crystal violet in 50% ethanol and counted, as previously described [29]. Only colonies comprising >50 cells were scored as survival colonies.…”

Section: Methodsmentioning

confidence: 99%

Ellagic Acid Inhibits Bladder Cancer Invasiveness and In Vivo Tumor Growth

et al. 2016

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Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.

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“…B. MAP ("mitogen-activated protein")-Kinase-Signalweg, Serin-Threoninkinase BRAF ("B rapidly accelerated fibrosarcoma") oder das G-Protein NRAS ("Neuroblastoma RAS viral oncogene homolog"). Die Molekularpathologie kann durch diese Identifikation neue Therapieoptionen ermöglichen [12,16].…”

Section: Hereditäre Aspekteunclassified