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26.06.2019 | PRECLINICAL STUDIES

Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells

verfasst von: Maria Chiara Proto, Donatella Fiore, Giovanni Forte, Paola Cuozzo, Anna Ramunno, Caterina Fattorusso, Patrizia Gazzerro, Maria Pascale, Silvia Franceschelli

Erschienen in: Investigational New Drugs | Ausgabe 3/2020

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Summary

Cutaneous melanoma, the most aggressive form of skin cancer, is characterized by activating BRAF mutations. Despite the initial success of selective BRAF inhibitors, only few patients exhibited complete responses, whereas many showed disease progression. Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16^INK4A and p14^ARF, two tumor suppressor genes. In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives, 8 g, 8 h and 8i, in melanoma cell lines, and we compared the effects of the most active of these, the 8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that 8i potentiates the inhibitory effect of Nutlin 3 and the combined use of 8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the 8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 transcriptional activity could be mediated by HSP90. Because the main feature of melanoma is the resistance to most chemotherapeutics, our studies suggest that the 8i tetra-substituted pyrrole derivative, restoring p53 functions and its transcriptional activities, may have potential application, at least as adjuvant, in the treatment of human melanoma.

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Haluska FG, Tsao H, Wu H, Haluska FS, Lazar A, Goel V (2006) Genetic alterations in signaling pathways in melanoma. Clin Cancer Res 12(7 Pt 2):2301s–2307s. https://doi.org/10.1158/1078-0432.CCR-14-1215 CrossRefPubMed

Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N (2012) The role of BRAF V600 mutation in melanoma. J Transl Med 10:85. https://doi.org/10.1186/1479-5876-10-85 CrossRefPubMedPubMedCentral

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur G, BRIM-3 Study Group. (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516. https://doi.org/10.1056/NEJMoa1103782

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365. https://doi.org/10.1016/S0140-6736(12)60868-X CrossRefPubMed

Fedorenko IV, Paraiso KH, Smalley KS (2011) Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol 82(3):201–209. https://doi.org/10.1016/j.bcp.2011.05.015 CrossRefPubMedPubMedCentral

Poulikakos PI, Solit DB (2011) Resistance to MEK inhibitors: should we co-target upstream? Sci Signal 4(166):pe16. https://doi.org/10.1126/scisignal.2001948 CrossRefPubMed

Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, DiCara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DSB, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263. https://doi.org/10.1016/j.cell.2012.06.024 CrossRefPubMedPubMedCentral

Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, Haupt Y, Larue L, Jochemsen A, Shi H, Moriceau G, Lo RS, Ghanem G, Shackleton M, Bernal F, Marine JC (2012) MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18(8):1239–1247. https://doi.org/10.1038/nm.2863 CrossRefPubMed

Murray-Zmijewski F, Slee EA, Lu X (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9(9):702–712. https://doi.org/10.1038/nrm2451 CrossRefPubMed

10.

Fischer M (2017) Census and evaluation of p53 target genes. Oncogene 36(28):3943–3956. https://doi.org/10.1038/onc.2016.502 CrossRefPubMedPubMedCentral

11.

Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848. https://doi.org/10.1126/science.1092472 CrossRefPubMed

12.

Ji Z, Njauw CN, Taylor M, Neel V, Flaherty KT, Tsao H (2012) p53 rescue through HDM2 antagonism suppresses melanoma growth and potentiates MEK inhibition. J Invest Dermatol 132(2):356–364. https://doi.org/10.1038/jid.2011.313 CrossRefPubMed

13.

Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, Ratnayaka I, Sullivan A, Brown NR, Endicott J, Knapp S, Kessler BM, Middleton MR, Siebold C, Jones EY, Sviderskaya EV, Cebon J, John T, Caballero OL, Goding CR, Lu X (2013) Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell 23(5):618–633. https://doi.org/10.1016/j.ccr.2013.03.013 CrossRefPubMed

14.

Persico M, Ramunno A, Maglio V, Franceschelli S, Esposito C, Carotenuto A, Brancaccio D, De Pasquale V, Pavone LM, Varra M, Orteca N, Novellino E, Fattorusso C (2013) New anticancer agents mimicking protein recognition motifs. J Med Chem 56(17):6666–6680. https://doi.org/10.1021/jm400947b CrossRefPubMed

15.

Hind CK, Carter MJ, Harris CL, Chan HT, James S, Cragg MS (2015) Role of the pro-survival molecule Bfl-1 in melanoma. Int J Biochem Cell Biol 59:94–102. https://doi.org/10.1016/j.biocel.2014.11.015 CrossRefPubMed

16.

Esposito T, Sansone F, Franceschelli S, Del Gaudio P, Picerno P, Aquino RP, Mencherini T (2017) Hazelnut (Corylus avellana L.) shells extract: phenolic composition, antioxidant effect and cytotoxic activity on human Cancer cell lines. Int J Mol Sci 18(2). pii: E392. https://doi.org/10.3390/ijms18020392

17.

Piccinelli AL, Pagano I, Esposito T, Mencherini T, Porta A, Petrone AM, Gazzerro P, Picerno P, Sansone F, Rastrelli L, Aquino RP (2016) HRMS profile of a hazelnut skin Proanthocyanidin-rich fraction with antioxidant and anti-Candida albicans activities. J Agric Food Chem 64(3):585–595. https://doi.org/10.1021/acs.jafc.5b05404 CrossRefPubMed

18.

Proto MC, Gazzerro P, Di Croce L, Santoro A, Malfitano AM, Pisanti S, Laezza C, Bifulco M (2012) Interaction of endocannabinoid system and steroid hormones in the control of colon cancer cell growth. J Cell Physiol 227(1):250–258. https://doi.org/10.1002/jcp.22727 CrossRefPubMed

19.

Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55CrossRef

20.

Gazzerro P, Malfitano AM, Proto MC, Santoro A, Pisanti S, Caruso MG, Notarnicola M, Messa C, Laezza C, Misso G, Caraglia M, Bifulco M (2010) Synergistic inhibition of human colon cancer cell growth by the cannabinoid CB1 receptor antagonist rimonabant and oxaliplatin. Oncol Rep 23(1):171–175PubMed

21.

Fiore D, Ramesh P, Proto MC, Piscopo C, Franceschelli S, Anzelmo S, Medema JP, Bifulco M, Gazzerro P (2018) Rimonabant kills Colon Cancer stem cells without inducing toxicity in Normal Colon organoids. Front Pharmacol 8:949. https://doi.org/10.3389/fphar.2017.00949 CrossRefPubMedPubMedCentral

22.

Proto MC, Fiore D, Piscopo C, Franceschelli S, Bizzarro V, Laezza C, Lauro G, Feoli A, Tosco A, Bifulco G, Sbardella G, Bifulco M, Gazzerro P (2017) Inhibition of Wnt/β-catenin pathway and histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer. Sci Rep 7(1):11678. https://doi.org/10.1038/s41598-017-11688-x CrossRefPubMedPubMedCentral

23.

Dal Piaz F, Cotugno R, Lepore L, Vassallo A, Malafronte N, Lauro G, Bifulco G, Belisario MA, De Tommasi N (2013) Chemical proteomics reveals HSP70 1A as a target for the anticancer diterpene oridonin in Jurkat cells. J Proteome 82:14–26. https://doi.org/10.1016/j.jprot.2013.01.030 CrossRef

24.

Dal Piaz F, Vera Saltos MB, Franceschelli S, Forte G, Marzocco S, Tuccinardi T, Poli G, Nejad Ebrahimi S, Hamburger M, De Tommasi N, Braca A (2016) Drug affinity responsive target stability (DARTS) identifies Laurifolioside as a new Clathrin heavy chain modulator. J Nat Prod 79(10):2681–2692. https://doi.org/10.1021/acs.jnatprod.6b00627 CrossRefPubMed

25.

Shangary S, Wang S (2009) Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 49:223–241. https://doi.org/10.1146/annurev.pharmtox.48.113006.094723 CrossRefPubMedPubMedCentral

26.

van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ, Laín S (2011) Mechanism-specific signatures for small-molecule p53 activators. Cell Cycle 10:1590–1598CrossRef

27.

de Lange J, Ly LV, Lodder K, Verlaan-de Vries M, Teunisse AF, Jager MJ, Jochemsen AG (2012) Synergistic growth inhibition based on small-molecule p53 activation as treatment for intraocular melanoma. Oncogene 31(9):1105–1116. https://doi.org/10.1038/onc.2011.309 CrossRefPubMed

28.

Pai MY, Lomenick B, Hwang H, Schiestel R, McBride W, Loo JA, Huang J (2015) Drug affinity responsive target stability (DARTS) for small-molecule target identification. Methods Mol Biol 1263:287–298. https://doi.org/10.1007/978-1-493-2269-7_22 CrossRefPubMedPubMedCentral

29.

Arthur CR, Gupton JT, Kellogg GE, Yeudall WA, Cabot MC, Newsham IF, Gewirtz DA (2007) Autophagic cell death, polyploidy and senescence induced in breast tumor cells by the substituted pyrrole JG-03-14, a novel microtubule poison. Biochem Pharmacol 74(7):981–991CrossRef

30.

Yoshii SR and Mizushima N ( 2017) Monitoring and measuring autophagy. Int J Mol Sci 18(9). Pii: E1865. https://doi.org/10.3390/ijms18091865

31.

Manzano JL, Layos L, Bugés C, de Los Llanos Gil M, Vila L, Martínez-Balibrea E, Martínez-Cardús A (2016) Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med 4(12):237. https://doi.org/10.21037/atm.2016.06.07

32.

Griffin M, Scotto D, Josephs DH, Mele S, Crescioli S, Bax HJ, Pellizzari G, Wynne MD, Nakamura M, Hoffmann RM, Ilieva KM, Cheung A, Spicer JF, Papa S, Lacy KE, Karagiannis SN (2017) BRAF inhibitors: resistance and the promise of combination treatments for melanoma. Oncotarget 8(44):78174–78192. https://doi.org/10.18632/oncotarget.19836 CrossRefPubMedPubMedCentral

33.

Hocker T, Tsao H (2007) Ultraviolet radiation and melanoma: a systemic review and analysis of reported sequence variants. Hum Mutat 28:588CrossRef

34.

Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP (2009) Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9(12):862–873. https://doi.org/10.1038/nrc2763 CrossRefPubMed

35.

Lu M, Miller P, Lu X (2014) Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy. FEBS Lett 588(16):2616–2621. https://doi.org/10.1016/j.febslet.2014.05.008 CrossRefPubMed

36.

Hata AN, Rowley S, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Ji F, Jung J, Light M, Lee JS, Debussche L, Sidhu S, Sadreyev RI, Watters J, Engelman JA (2017) Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers. Oncogene 36(47):6581–6591. https://doi.org/10.1038/onc.2017.258 CrossRefPubMedPubMedCentral

37.

Smalley KS, Contractor R, Haass NK, Kulp AN, Atilla-Gokcumen GE, Williams DS, Bregman H, Flaherty KT, Soengas MS, Meggers E, Herlyn M (2007) An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res 67(1):209–217. https://doi.org/10.1158/0008-5472.CAN-06-1538 CrossRefPubMed

38.

Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT (2006) Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A 103(6):1888–1893. https://doi.org/10.1073/pnas.0507493103 CrossRefPubMedPubMedCentral

39.

Ji Z, Kumar R, Taylor M, Rajadurai A, Marzuka-Alcalá A, Chen YE, Njauw CN, Flaherty K, Jönsson G, Tsao H (2013) Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth. Clin Cancer Res 19(16):4383–4391. https://doi.org/10.1158/1078-0432.CCR-13-0074 CrossRefPubMedPubMedCentral

40.

Sutton SK, Carter DR, Kim P, Tan O, Arndt GM, Zhang XD, Baell J, Noll BD, Wang S, Kumar N, McArthur GA, Cheung BB, Marshall GM (2016) A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner. Oncotarget 7(32):52166–52178. https://doi.org/10.18632/oncotarget.10700 CrossRefPubMedPubMedCentral

41.

Agaësse G, Barbollat-Boutrand L, El Kharbili M, Berthier-Vergnes O, Masse I (2017) p53 targets TSPAN8 to prevent invasion in melanoma cells. Oncogenesis. 6(4):e309. https://doi.org/10.1038/oncsis.2017.11 CrossRefPubMedPubMedCentral

42.

Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL, Meyer T (2013) The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155(2):369–383. https://doi.org/10.1016/j.cell.2013.08.062 CrossRefPubMedPubMedCentral

43.

Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772. https://doi.org/10.1038/nrc1716 CrossRefPubMed

44.

Schopf FH, Biebl MM, Buchner J (2017) The HSP90 chaperone machinery. Nat Rev Mol Cell Biol 18(6):345–360. https://doi.org/10.1038/nrm.2017.20 CrossRefPubMed

45.

Blagosklonny MV, Toretsky J, Bohen S, Neckers L (1996) Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90. Proc Natl Acad Sci U S A 93(16):8379–8383CrossRef

46.

Hagn F, Lagleder S, Retzlaff M, Rohrberg J, Demmer O, Richter K, Buchner J, Kessler H (2011) Structural analysis of the interaction between Hsp90 and the tumor suppressor protein p53. Nat Struct Mol Biol 18(10):1086–1093. https://doi.org/10.1038/nsmb.2114 CrossRefPubMed

47.

Müller L, Schaupp A, Walerych D, Wegele H, Buchner J (2004) Hsp90 regulates the activity of wild type p53 under physiological and elevated temperatures. J Biol Chem 279(47):48846–48854. https://doi.org/10.1074/jbc.M407687200 CrossRefPubMed

48.

Walerych D, Kudla G, Gutkowska M, Wawrzynow B, Muller L, King FW, Helwak A, Boros J, Zylicz A, Zylicz M (2004) Hsp90 chaperones wild-type p53 tumor suppressor protein. J Biol Chem 279(47):48836–48845. https://doi.org/10.1074/jbc.M407601200 CrossRefPubMed

49.

Acquaviva J, Smith DL, Jimenez JP, Zhang C, Sequeira M, He S, Sang J, Bates RC, Proia DA (2014) Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Mol Cancer Ther 13(2):353–363. https://doi.org/10.1158/1535-7163.MCT-13-0481 CrossRefPubMed

50.

Mbofung RM, McKenzie JA, Malu S, Zhang M, Peng W, Liu C et al (2017) HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nat Commun 8(1):451. https://doi.org/10.1038/s41467-017-00449-z CrossRefPubMedPubMedCentral

51.

Tseng HY, Jiang CC, Croft A, Tay KH, Thorne RF, Yang F, Liu H, Hersey P, Zhang XD (2010) Contrasting effects of nutlin-3 on TRAIL- and docetaxel-induced apoptosis due to upregulation of TRAIL-R2 and Mcl-1 in human melanoma cells. Mol Cancer Ther 9(12):3363–3374. https://doi.org/10.1158/1535-7163.MCT-10-0646 CrossRefPubMed

52.

Tokalov SV, Abolmaali ND (2010) Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment. BMC Cancer 10:57CrossRef

53.

Huang B, Deo D, Xia M, Vassilev LT (2009) Pharmacologic p53 activation blocks cell cycle progression but fails to induce senescence in epithelial cancer cells. Mol Cancer Res 7:1497–1509CrossRef

54.

Boisvert-Adamo K, Longmate W, Abel EV, Aplin AE (2009) Mcl-1 is required for melanoma cell resistance to anoikis. Mol Cancer Res 7(4):549–556. https://doi.org/10.1158/1541-7786.MCR-08-0358 CrossRefPubMedPubMedCentral

55.

Borthakur G, Duvvuri S, Ruvolo V, Tripathi DN, Piya S, Burks J, Jacamo R, Kojima K, Ruvolo P, Fueyo-Margareto J, Konopleva M, Andreeff M (2015) MDM2 inhibitor, Nutlin 3a, induces p53 dependent autophagy in acute leukemia by AMP kinase activation. PLoS One 10(10):e0139254. https://doi.org/10.1371/journal.pone.0139254 CrossRefPubMedPubMedCentral

56.

Davaadelger B, Perez RE, Zhou Y, Duan L, Gitelis S, Maki CG (2017) The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis. Cancer Biol Ther 18(11):895–903. https://doi.org/10.1080/15384047.2017.1345397 CrossRefPubMedPubMedCentral

57.

Vincent KM, Postovit LM (2017) Investigating the utility of human melanoma cell lines as tumour models. Oncotarget 8(6):10498–10509. https://doi.org/10.18632/oncotarget.14443 CrossRefPubMed

Titel: Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells
verfasst von: Maria Chiara Proto
Donatella Fiore
Giovanni Forte
Paola Cuozzo
Anna Ramunno
Caterina Fattorusso
Patrizia Gazzerro
Maria Pascale
Silvia Franceschelli
Publikationsdatum: 26.06.2019
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 3/2020
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00813-4

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Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells

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ICI-Therapie in der Schwangerschaft wird gut toleriert

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