The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

A. De Luca, D. Carpanese, M.C. Rapanotti, T.M. Suarez Viguria, M.A. Forgione, D. Rotili, C. Fulci, E. Iorio, L. Quintieri, S. Chimenti, L. Bianchi, A. Rosato, A.M. Caccuri

Research output: Contribution to journalArticle

Abstract

The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenibresistant 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.
Original languageEnglish
Pages (from-to)15520-15538
Number of pages19
JournalOncotarget
Volume8
Issue number9
Publication statusPublished - 2017

Fingerprint

Melanoma
Transcription Factor AP-2
Cellular Spheroids
Neoplasm Metastasis
Cell Line
Experimental Melanomas
Cadherins
Matrix Metalloproteinases
Heterografts
Pharmaceutical Preparations
Vascular Endothelial Growth Factor A
Lactic Acid
Lung
Skin
Survival
Therapeutics
Neoplasms
Proteins

Keywords

  • 6-((7-nitrobenzo[c][1,2,5]oxadiazoles
  • Antimetastatic properties
  • C-Jun N-terminal kinase
  • Glutathione transferase P1-1
  • Melanoma
  • 2 [2 [2 [(7 nitrobenzo[c][1,2,5]oxadiazol 4 yl)thio]ethoxy]ethoxy]ethanol
  • antineoplastic agent
  • aspartic acid
  • B Raf kinase
  • CD146 antigen
  • gelatinase A
  • lactic acid
  • mitogen activated protein kinase
  • nerve cell adhesion molecule
  • stress activated protein kinase
  • temozolomide
  • transcription factor AP 2
  • unclassified drug
  • valine
  • vasculotropin
  • vemurafenib
  • BRAF protein, human
  • MC3181
  • nitrobenzene derivative
  • oxadiazole derivative
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • biosynthesis
  • cancer inhibition
  • cancer patient
  • cancer survival
  • cell count
  • concentration response
  • controlled study
  • drug mechanism
  • enzyme activation
  • glycolysis
  • human
  • human cell
  • in vivo study
  • lung metastasis
  • male
  • melanoma
  • melanoma cell line
  • metastasis inhibition
  • monolayer culture
  • mouse
  • nonhuman
  • protein expression
  • tumor invasion
  • tumor spheroid
  • tumor vascularization
  • WM115 cell line
  • WM266.4 cell line
  • animal
  • cell culture technique
  • cell motion
  • cell proliferation
  • cell survival
  • chemistry
  • drug effects
  • gene expression regulation
  • genetics
  • immunoblotting
  • Lung Neoplasms
  • Melanoma, Experimental
  • metabolism
  • multicellular spheroid
  • mutation
  • pathology
  • reverse transcription polymerase chain reaction
  • secondary
  • skin tumor
  • tumor cell line
  • Animals
  • Antigens, CD146
  • Antineoplastic Agents
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Mice
  • Mitogen-Activated Protein Kinases
  • Mutation
  • Neoplasm Invasiveness
  • Nitrobenzenes
  • Oxadiazoles
  • Proto-Oncogene Proteins B-raf
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms
  • Spheroids, Cellular

Cite this

De Luca, A., Carpanese, D., Rapanotti, M. C., Suarez Viguria, T. M., Forgione, M. A., Rotili, D., ... Caccuri, A. M. (2017). The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. Oncotarget, 8(9), 15520-15538.

The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. / De Luca, A.; Carpanese, D.; Rapanotti, M.C.; Suarez Viguria, T.M.; Forgione, M.A.; Rotili, D.; Fulci, C.; Iorio, E.; Quintieri, L.; Chimenti, S.; Bianchi, L.; Rosato, A.; Caccuri, A.M.

In: Oncotarget, Vol. 8, No. 9, 2017, p. 15520-15538.

Research output: Contribution to journalArticle

De Luca, A, Carpanese, D, Rapanotti, MC, Suarez Viguria, TM, Forgione, MA, Rotili, D, Fulci, C, Iorio, E, Quintieri, L, Chimenti, S, Bianchi, L, Rosato, A & Caccuri, AM 2017, 'The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis', Oncotarget, vol. 8, no. 9, pp. 15520-15538.
De Luca A, Carpanese D, Rapanotti MC, Suarez Viguria TM, Forgione MA, Rotili D et al. The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. Oncotarget. 2017;8(9):15520-15538.
De Luca, A. ; Carpanese, D. ; Rapanotti, M.C. ; Suarez Viguria, T.M. ; Forgione, M.A. ; Rotili, D. ; Fulci, C. ; Iorio, E. ; Quintieri, L. ; Chimenti, S. ; Bianchi, L. ; Rosato, A. ; Caccuri, A.M. / The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis. In: Oncotarget. 2017 ; Vol. 8, No. 9. pp. 15520-15538.
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title = "The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis",
abstract = "The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenibresistant 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.",
keywords = "6-((7-nitrobenzo[c][1,2,5]oxadiazoles, Antimetastatic properties, C-Jun N-terminal kinase, Glutathione transferase P1-1, Melanoma, 2 [2 [2 [(7 nitrobenzo[c][1,2,5]oxadiazol 4 yl)thio]ethoxy]ethoxy]ethanol, antineoplastic agent, aspartic acid, B Raf kinase, CD146 antigen, gelatinase A, lactic acid, mitogen activated protein kinase, nerve cell adhesion molecule, stress activated protein kinase, temozolomide, transcription factor AP 2, unclassified drug, valine, vasculotropin, vemurafenib, BRAF protein, human, MC3181, nitrobenzene derivative, oxadiazole derivative, animal experiment, animal model, animal tissue, Article, biosynthesis, cancer inhibition, cancer patient, cancer survival, cell count, concentration response, controlled study, drug mechanism, enzyme activation, glycolysis, human, human cell, in vivo study, lung metastasis, male, melanoma, melanoma cell line, metastasis inhibition, monolayer culture, mouse, nonhuman, protein expression, tumor invasion, tumor spheroid, tumor vascularization, WM115 cell line, WM266.4 cell line, animal, cell culture technique, cell motion, cell proliferation, cell survival, chemistry, drug effects, gene expression regulation, genetics, immunoblotting, Lung Neoplasms, Melanoma, Experimental, metabolism, multicellular spheroid, mutation, pathology, reverse transcription polymerase chain reaction, secondary, skin tumor, tumor cell line, Animals, Antigens, CD146, Antineoplastic Agents, Cell Culture Techniques, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, Mice, Mitogen-Activated Protein Kinases, Mutation, Neoplasm Invasiveness, Nitrobenzenes, Oxadiazoles, Proto-Oncogene Proteins B-raf, Reverse Transcriptase Polymerase Chain Reaction, Skin Neoplasms, Spheroids, Cellular",
author = "{De Luca}, A. and D. Carpanese and M.C. Rapanotti and {Suarez Viguria}, T.M. and M.A. Forgione and D. Rotili and C. Fulci and E. Iorio and L. Quintieri and S. Chimenti and L. Bianchi and A. Rosato and A.M. Caccuri",
note = "Cited By :2 Export Date: 6 April 2018 Correspondence Address: Caccuri, A.M.; Department of Experimental Medicine and Surgery, University of Tor VergataItaly; email: caccuri@uniroma2.it Chemicals/CAS: aspartic acid, 56-84-8, 6899-03-2; gelatinase A, 146480-35-5; lactic acid, 113-21-3, 50-21-5; mitogen activated protein kinase, 142243-02-5; stress activated protein kinase, 155215-87-5; temozolomide, 85622-93-1; valine, 7004-03-7, 72-18-4; vasculotropin, 127464-60-2; vemurafenib, 918504-65-1; Antigens, CD146; Antineoplastic Agents; BRAF protein, human; MC3181; Mitogen-Activated Protein Kinases; Nitrobenzenes; Oxadiazoles; Proto-Oncogene Proteins B-raf Tradenames: MC 3181 Manufacturers: Selleck, Germany; Sigma Aldrich, Italy References: Haier, J., Nicolson, G.L., Tumor cell adhesion under hydrodynamic conditions of fluid flow (2001) APMIS: acta pathologica, microbiologica, et immunologica Scandinavica, 109, pp. 241-262; Chambers, A.F., Groom, A.C., MacDonald, I.C., Dissemination and growth of cancer cells in metastatic sites (2002) Nature reviews Cancer, 2, pp. 563-572; Nguyen, D.X., Bos, P.D., Massague, J., Metastasis: from dissemination to organ-specific colonization (2009) Nature reviews Cancer, 9, pp. 274-284; Morris, E.J., Jha, S., Restaino, C.R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Zhao, S., Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors (2013) Cancer Discov, 3, pp. 742-750; Graziani, G., Artuso, S., De Luca, A., Muzi, A., Rotili, D., Scimeca, M., Atzori, M.G., Caccuri, A.M., A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib (2015) Biochemical pharmacology, 95, pp. 16-27; De Luca, A., Rotili, D., Carpanese, D., Lenoci, A., Calderan, L., Scimeca, M., Mai, A., Caccuri, A.M., A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts (2015) Oncotarget, 6, pp. 4126-4143; Smalley, K.S., Lioni, M., Noma, K., Haass, N.K., Herlyn, M., In vitro three-dimensional tumor microenvironment models for anticancer drug discovery (2008) Expert opinion on drug discovery, 3, pp. 1-10; Chan, G.K., Kleinheinz, T.L., Peterson, D., Moffat, J.G., A simple high-content cell cycle assay reveals frequent discrepancies between cell number and ATP and MTS proliferation assays (2013) PloS one, 8; Haier, J., Nicolson, G.L., Tumor cell adhesion under hydrodynamic conditions of fluid flow (2001) APMIS: acta pathologica, microbiologica, et immunologica Scandinavica, 109, pp. 241-262; Chambers, A.F., Groom, A.C., MacDonald, I.C., Dissemination and growth of cancer cells in metastatic sites (2002) Nature reviews Cancer, 2, pp. 563-572; Nguyen, D.X., Bos, P.D., Massague, J., Metastasis: from dissemination to organ-specific colonization (2009) Nature reviews Cancer, 9, pp. 274-284; Morris, E.J., Jha, S., Restaino, C.R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Zhao, S., Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors (2013) Cancer Discov, 3, pp. 742-750; Graziani, G., Artuso, S., De Luca, A., Muzi, A., Rotili, D., Scimeca, M., Atzori, M.G., Caccuri, A.M., A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib (2015) Biochemical pharmacology, 95, pp. 16-27; De Luca, A., Rotili, D., Carpanese, D., Lenoci, A., Calderan, L., Scimeca, M., Mai, A., Caccuri, A.M., A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts (2015) Oncotarget, 6, pp. 4126-4143; Smalley, K.S., Lioni, M., Noma, K., Haass, N.K., Herlyn, M., In vitro three-dimensional tumor microenvironment models for anticancer drug discovery (2008) Expert opinion on drug discovery, 3, pp. 1-10; Chan, G.K., Kleinheinz, T.L., Peterson, D., Moffat, J.G., A simple high-content cell cycle assay reveals frequent discrepancies between cell number and ATP and MTS proliferation assays (2013) PloS one, 8. , response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res. 2011; 9:115-130; Park, H., Jeoung, N.H., Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the Jun N-Terminal Kinase (JNK) pathway in C2C12 cells (2016) Biochem. Biophys. Res. Commun, 469, pp. 1049-1054; Gaubatz, S., Imhof, A., Dosch, R., Werner, O., Mitchell, P., Buettner, R., Eilers, M., Transcriptional activation by Myc is under negative control by the transcription factor AP-2 (1995) EMBO J, 14, pp. 1508-1519; Ricci, G., De Maria, F., Antonini, G., Turella, P., Bullo, A., Stella, L., Filomeni, G., Caccuri, A.M., 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs (2005) The Journal of biological chemistry, 280, pp. 26397-26405; Iorio, E., Ricci, A., Bagnoli, M., Pisanu, M.E., Castellano, G., Di Vito, M., Venturini, E., Podo, F., Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells (2010) Cancer research, 70, pp. 2126-2135; Iorio, E., Mezzanzanica, D., Alberti, P., Spadaro, F., Ramoni, C., D'Ascenzo, S., Millimaggi, D., Podo, F., Alterations of choline phospholipid metabolism in ovarian tumor progression (2005) Cancer research, 65, pp. 9369-9376; Chomczynski, P., Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction (1987) Analytical biochemistry, 162, pp. 156-159; Alais, S., Allioli, N., Pujades, C., Duband, J.L., Vainio, O., Imhof, B.A., Dunon, D., HEMCAM/CD146 downregulates cell surface expression of beta1 integrins (2001) Journal of cell science, 114, pp. 1847-1859; Rapanotti, M.C., Bianchi, L., Ricozzi, I., Campione, E., Pierantozzi, A., Orlandi, A., Chimenti, S., Bernardini, S., Melanoma-associated markers expression in blood: MUC-18 is associated with advanced stages in melanoma patients (2009) The British journal of dermatology, 160, pp. 338-344; Rapanotti, M.C., Suarez Viguria, T.M., Costanza, G., Ricozzi, I., Pierantozzi, A., Di Stefani, A., Campione, E., Bianchi, L., Sequential molecular analysis of circulating MCAM/MUC18 expression: a promising disease biomarker related to clinical outcome in melanoma (2014) Archives of dermatological research, 306, pp. 527-537; Hagen, R.M., Rhodes, A., Oxley, J., Ladomery, M.R., A M-MLV reverse transcriptase with reduced RNaseH activity allows greater sensitivity of gene expression detection in formalin fixed and paraffin embedded prostate cancer samples (2013) Exp Mol Pathol, 95, pp. 98-104",
year = "2017",
language = "English",
volume = "8",
pages = "15520--15538",
journal = "Oncotarget",
issn = "1949-2553",
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}

TY - JOUR

T1 - The nitrobenzoxadiazole derivative MC3181 blocks melanoma invasion and metastasis

AU - De Luca, A.

AU - Carpanese, D.

AU - Rapanotti, M.C.

AU - Suarez Viguria, T.M.

AU - Forgione, M.A.

AU - Rotili, D.

AU - Fulci, C.

AU - Iorio, E.

AU - Quintieri, L.

AU - Chimenti, S.

AU - Bianchi, L.

AU - Rosato, A.

AU - Caccuri, A.M.

N1 - Cited By :2 Export Date: 6 April 2018 Correspondence Address: Caccuri, A.M.; Department of Experimental Medicine and Surgery, University of Tor VergataItaly; email: caccuri@uniroma2.it Chemicals/CAS: aspartic acid, 56-84-8, 6899-03-2; gelatinase A, 146480-35-5; lactic acid, 113-21-3, 50-21-5; mitogen activated protein kinase, 142243-02-5; stress activated protein kinase, 155215-87-5; temozolomide, 85622-93-1; valine, 7004-03-7, 72-18-4; vasculotropin, 127464-60-2; vemurafenib, 918504-65-1; Antigens, CD146; Antineoplastic Agents; BRAF protein, human; MC3181; Mitogen-Activated Protein Kinases; Nitrobenzenes; Oxadiazoles; Proto-Oncogene Proteins B-raf Tradenames: MC 3181 Manufacturers: Selleck, Germany; Sigma Aldrich, Italy References: Haier, J., Nicolson, G.L., Tumor cell adhesion under hydrodynamic conditions of fluid flow (2001) APMIS: acta pathologica, microbiologica, et immunologica Scandinavica, 109, pp. 241-262; Chambers, A.F., Groom, A.C., MacDonald, I.C., Dissemination and growth of cancer cells in metastatic sites (2002) Nature reviews Cancer, 2, pp. 563-572; Nguyen, D.X., Bos, P.D., Massague, J., Metastasis: from dissemination to organ-specific colonization (2009) Nature reviews Cancer, 9, pp. 274-284; Morris, E.J., Jha, S., Restaino, C.R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Zhao, S., Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors (2013) Cancer Discov, 3, pp. 742-750; Graziani, G., Artuso, S., De Luca, A., Muzi, A., Rotili, D., Scimeca, M., Atzori, M.G., Caccuri, A.M., A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib (2015) Biochemical pharmacology, 95, pp. 16-27; De Luca, A., Rotili, D., Carpanese, D., Lenoci, A., Calderan, L., Scimeca, M., Mai, A., Caccuri, A.M., A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts (2015) Oncotarget, 6, pp. 4126-4143; Smalley, K.S., Lioni, M., Noma, K., Haass, N.K., Herlyn, M., In vitro three-dimensional tumor microenvironment models for anticancer drug discovery (2008) Expert opinion on drug discovery, 3, pp. 1-10; Chan, G.K., Kleinheinz, T.L., Peterson, D., Moffat, J.G., A simple high-content cell cycle assay reveals frequent discrepancies between cell number and ATP and MTS proliferation assays (2013) PloS one, 8; Haier, J., Nicolson, G.L., Tumor cell adhesion under hydrodynamic conditions of fluid flow (2001) APMIS: acta pathologica, microbiologica, et immunologica Scandinavica, 109, pp. 241-262; Chambers, A.F., Groom, A.C., MacDonald, I.C., Dissemination and growth of cancer cells in metastatic sites (2002) Nature reviews Cancer, 2, pp. 563-572; Nguyen, D.X., Bos, P.D., Massague, J., Metastasis: from dissemination to organ-specific colonization (2009) Nature reviews Cancer, 9, pp. 274-284; Morris, E.J., Jha, S., Restaino, C.R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Zhao, S., Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors (2013) Cancer Discov, 3, pp. 742-750; Graziani, G., Artuso, S., De Luca, A., Muzi, A., Rotili, D., Scimeca, M., Atzori, M.G., Caccuri, A.M., A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib (2015) Biochemical pharmacology, 95, pp. 16-27; De Luca, A., Rotili, D., Carpanese, D., Lenoci, A., Calderan, L., Scimeca, M., Mai, A., Caccuri, A.M., A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts (2015) Oncotarget, 6, pp. 4126-4143; Smalley, K.S., Lioni, M., Noma, K., Haass, N.K., Herlyn, M., In vitro three-dimensional tumor microenvironment models for anticancer drug discovery (2008) Expert opinion on drug discovery, 3, pp. 1-10; Chan, G.K., Kleinheinz, T.L., Peterson, D., Moffat, J.G., A simple high-content cell cycle assay reveals frequent discrepancies between cell number and ATP and MTS proliferation assays (2013) PloS one, 8. , response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res. 2011; 9:115-130; Park, H., Jeoung, N.H., Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the Jun N-Terminal Kinase (JNK) pathway in C2C12 cells (2016) Biochem. Biophys. Res. Commun, 469, pp. 1049-1054; Gaubatz, S., Imhof, A., Dosch, R., Werner, O., Mitchell, P., Buettner, R., Eilers, M., Transcriptional activation by Myc is under negative control by the transcription factor AP-2 (1995) EMBO J, 14, pp. 1508-1519; Ricci, G., De Maria, F., Antonini, G., Turella, P., Bullo, A., Stella, L., Filomeni, G., Caccuri, A.M., 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs (2005) The Journal of biological chemistry, 280, pp. 26397-26405; Iorio, E., Ricci, A., Bagnoli, M., Pisanu, M.E., Castellano, G., Di Vito, M., Venturini, E., Podo, F., Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells (2010) Cancer research, 70, pp. 2126-2135; Iorio, E., Mezzanzanica, D., Alberti, P., Spadaro, F., Ramoni, C., D'Ascenzo, S., Millimaggi, D., Podo, F., Alterations of choline phospholipid metabolism in ovarian tumor progression (2005) Cancer research, 65, pp. 9369-9376; Chomczynski, P., Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction (1987) Analytical biochemistry, 162, pp. 156-159; Alais, S., Allioli, N., Pujades, C., Duband, J.L., Vainio, O., Imhof, B.A., Dunon, D., HEMCAM/CD146 downregulates cell surface expression of beta1 integrins (2001) Journal of cell science, 114, pp. 1847-1859; Rapanotti, M.C., Bianchi, L., Ricozzi, I., Campione, E., Pierantozzi, A., Orlandi, A., Chimenti, S., Bernardini, S., Melanoma-associated markers expression in blood: MUC-18 is associated with advanced stages in melanoma patients (2009) The British journal of dermatology, 160, pp. 338-344; Rapanotti, M.C., Suarez Viguria, T.M., Costanza, G., Ricozzi, I., Pierantozzi, A., Di Stefani, A., Campione, E., Bianchi, L., Sequential molecular analysis of circulating MCAM/MUC18 expression: a promising disease biomarker related to clinical outcome in melanoma (2014) Archives of dermatological research, 306, pp. 527-537; Hagen, R.M., Rhodes, A., Oxley, J., Ladomery, M.R., A M-MLV reverse transcriptase with reduced RNaseH activity allows greater sensitivity of gene expression detection in formalin fixed and paraffin embedded prostate cancer samples (2013) Exp Mol Pathol, 95, pp. 98-104

PY - 2017

Y1 - 2017

N2 - The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenibresistant 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.

AB - The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenibresistant 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.

KW - 6-((7-nitrobenzo[c][1,2,5]oxadiazoles

KW - Antimetastatic properties

KW - C-Jun N-terminal kinase

KW - Glutathione transferase P1-1

KW - Melanoma

KW - 2 [2 [2 [(7 nitrobenzo[c][1,2,5]oxadiazol 4 yl)thio]ethoxy]ethoxy]ethanol

KW - antineoplastic agent

KW - aspartic acid

KW - B Raf kinase

KW - CD146 antigen

KW - gelatinase A

KW - lactic acid

KW - mitogen activated protein kinase

KW - nerve cell adhesion molecule

KW - stress activated protein kinase

KW - temozolomide

KW - transcription factor AP 2

KW - unclassified drug

KW - valine

KW - vasculotropin

KW - vemurafenib

KW - BRAF protein, human

KW - MC3181

KW - nitrobenzene derivative

KW - oxadiazole derivative

KW - animal experiment

KW - animal model

KW - animal tissue

KW - Article

KW - biosynthesis

KW - cancer inhibition

KW - cancer patient

KW - cancer survival

KW - cell count

KW - concentration response

KW - controlled study

KW - drug mechanism

KW - enzyme activation

KW - glycolysis

KW - human

KW - human cell

KW - in vivo study

KW - lung metastasis

KW - male

KW - melanoma

KW - melanoma cell line

KW - metastasis inhibition

KW - monolayer culture

KW - mouse

KW - nonhuman

KW - protein expression

KW - tumor invasion

KW - tumor spheroid

KW - tumor vascularization

KW - WM115 cell line

KW - WM266.4 cell line

KW - animal

KW - cell culture technique

KW - cell motion

KW - cell proliferation

KW - cell survival

KW - chemistry

KW - drug effects

KW - gene expression regulation

KW - genetics

KW - immunoblotting

KW - Lung Neoplasms

KW - Melanoma, Experimental

KW - metabolism

KW - multicellular spheroid

KW - mutation

KW - pathology

KW - reverse transcription polymerase chain reaction

KW - secondary

KW - skin tumor

KW - tumor cell line

KW - Animals

KW - Antigens, CD146

KW - Antineoplastic Agents

KW - Cell Culture Techniques

KW - Cell Line, Tumor

KW - Cell Movement

KW - Cell Proliferation

KW - Cell Survival

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunoblotting

KW - Mice

KW - Mitogen-Activated Protein Kinases

KW - Mutation

KW - Neoplasm Invasiveness

KW - Nitrobenzenes

KW - Oxadiazoles

KW - Proto-Oncogene Proteins B-raf

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Skin Neoplasms

KW - Spheroids, Cellular

M3 - Article

VL - 8

SP - 15520

EP - 15538

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 9

ER -