Inhibiting the “Undruggable” RAS/Farnesyltransferase (FTase) Cancer
Target by Manumycin-related Natural Products

Leandro    Rocha    Silva; Edeildo    Ferreira    da Silva-Júnior
doi:10.2174/0929867328666210315123848
Abstract

Cancer is an uncontrolled cell growth that can generate diverse types of cancer, in which these will also present a different behavior in the face of pharmacological treatment. These cancers’ types are found in one of the three categories, leukemias (also named lymphomas), carcinomas, and sarcomas. In general, cancer's pathogenesis is associated with three genetic mutations, where could emerge from oncogenes, tumor suppressor genes, and/or genes responsible for regulating DNA replication. The term “undruggable” is frequently related to the difficulty to design drugs to specific targets, such as MYC, MYB, NF-κB, and RAS family of proteins. This last comprises more than 140 proteins, and these are responsible for 30% of mutations in human cancers. Also, there are three ras genes transcribed in human cells, called H-, K-, and N-ras oncogenes. Still, the RAS proteins (farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) enzymes) perform essential steps in post-translational modification of eukaryotes cells, such as (1) the farnesylation of the cysteine residue at the C-terminal tetrapeptide CAAX; (2) proteolytic cleavage of the three C-terminal AAX oligopeptide; and (3) carboxymethylation of the new C-terminal prenylated cysteine. Thus, the inhibition of this undruggable RAS family of proteins has been considered a promising alternative to design new anticancer agents since they are responsible for many types of human cancers. Then, the manumycin A (obtained from the Streptomyces parvulus Tü64) and its analogs (epoxyquinol core with or without their southern and eastern side chains; and dihydroxycyclohexenones core) have been described as promising FTase inhibitors, which have demonstrated their benefits against several types of cancer. In this review, a complete introduction about cancer and its relation with RAS proteins is provided, as well as, the prenylation mechanism of the cysteine residue is discussed in detail. Posteriorly, studies involving manumycin-related compounds are described, showing some synthetic routes for obtaining them and utilizing these natural products in monotherapies or combined therapies with other anticancer drugs.
Keywords: Ras family, manumycin A, asukamycin, LL-C10037α, farnesyltransferase, geranylgeranyltransferase
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[1] 
Cooper, G.M. The Cell - A Molecular Approach, 2nd ed; Sinauer Associates: Sunderland, 2000. 
[2] 
Gibbs, J.B.; Oliff, A. Pharmaceutical research in molecular oncology. Cell,  1994, 79(2), 193-198.
[http://dx.doi.org/10.1016/0092-8674(94)90189-9] [PMID: 7954788] 
[3] 
Bollag, G.; McCormick, F. Regulators and effectors of ras proteins. Annu. Rev. Cell Biol.,  1991, 7, 601-632.
[http://dx.doi.org/10.1146/annurev.cb.07.110191.003125] [PMID: 1667084] 
[4] 
Lowy, D.R.; Willumsen, B.M. Function and regulation of ras. Annu. Rev. Biochem.,  1993, 62, 851-891.
[http://dx.doi.org/10.1146/annurev.bi.62.070193.004223] [PMID: 8352603] 
[5] 
Prendergast, G.C.; Oliff, A. Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects. Semin. Cancer Biol.,  2000, 10(6), 443-452.
[http://dx.doi.org/10.1006/scbi.2000.0335] [PMID: 11170866] 
[6] 
Boguski, M.S.; McCormick, F. Proteins regulating Ras and its relatives. Nature,  1993, 366(6456), 643-654.
[http://dx.doi.org/10.1038/366643a0] [PMID: 8259209] 
[7] 
Dang, C.V.; Reddy, E.P.; Shokat, K.M.; Soucek, L. Drugging the ‘undruggable’ cancer targets. Nat. Rev. Cancer,  2017, 17(8), 502-508.
[http://dx.doi.org/10.1038/nrc.2017.36] [PMID: 28643779] 
[8] 
Oliff, A. Farnesyltransferase inhibitors: targeting the molecular basis of cancer. Biochim. Biophys. Acta,  1999, 1423(3), C19-C30.
[http://dx.doi.org/10.1016/s0304-419x(99)00007-4] [PMID: 10382537] 
[9] 
Barbacid, M. Ras genes. Annu. Rev. Biochem.,  1987, 56, 779-827.
[http://dx.doi.org/10.1146/annurev.bi.56.070187.004023] [PMID: 3304147] 
[10] 
Tamanoi, F. Inhibitors of Ras farnesyltransferases. Trends Biochem. Sci.,  1993, 18(9), 349-353.
[http://dx.doi.org/10.1016/0968-0004(93)90072-U] [PMID: 8236454] 
[11] 
Kohl, N.E.; Mosser, S.D.; deSolms, S.J.; Giuliani, E.A.; Pompliano, D.L.; Graham, S.L.; Smith, R.L.; Scolnick, E.M.; Oliff, A.; Gibbs, J.B. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science,  1993, 260(5116), 1934-1937.
[http://dx.doi.org/10.1126/science.8316833] [PMID: 8316833] 
[12] 
Kohl, N.E.; Wilson, F.R.; Mosser, S.D.; Giuliani, E.; deSolms, S.J.; Conner, M.W.; Anthony, N.J.; Holtz, W.J.; Gomez, R.P.; Lee, T.J. Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc. Natl. Acad. Sci. USA,  1994, 91(19), 9141-9145.
[http://dx.doi.org/10.1073/pnas.91.19.9141] [PMID: 8090782] 
[13] 
James, G.L.; Goldstein, J.L.; Brown, M.S.; Rawson, T.E.; Somers, T.C.; McDowell, R.S.; Crowley, C.W.; Lucas, B.K.; Levinson, A.D.; Marsters, J.C., Jr Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science,  1993, 260(5116), 1937-1942.
[http://dx.doi.org/10.1126/science.8316834] [PMID: 8316834] 
[14] 
Loeffler, I.K.; Bennett, J.L. A rab-related GTP-binding protein in Schistosoma mansoni. Mol. Biochem. Parasitol.,  1996, 77(1), 31-40.
[http://dx.doi.org/10.1016/0166-6851(96)02579-0] [PMID: 8784769] 
[15] 
Luján, H.D.; Mowatt, M.R.; Chen, G-Z.; Nash, T.E. 
                        Isoprenylation of proteins in the protozoan
                        
                             Giardia lamblia
                        
                    .
                     Mol. Biochem. Parasitol.,  1995, 72(1-2), 121-127.
[http://dx.doi.org/10.1016/0166-6851(94)00070-4] [PMID: 8538683] 
[16] 
Yokoyama, K.; Trobridge, P.; Buckner, F.S.; Scholten, J.; Stuart, K.D.; Van Voorhis, W.C.; Gelb, M.H. The effects of protein farnesyltransferase inhibitors on trypanosomatids: inhibition of protein farnesylation and cell growth. Mol. Biochem. Parasitol.,  1998, 94(1), 87-97.
[http://dx.doi.org/10.1016/S0166-6851(98)00053-X] [PMID: 9719512] 
[17] 
Yokoyama, K.; Trobridge, P.; Buckner, F.S.; Van Voorhis, W.C.; Stuart, K.D.; Gelb, M.H. 
                        Protein farnesyltransferase from 
                        
                            Trypanosoma brucei
                        
                    . A heterodimer of 61- and 65-kda subunits as a new target for antiparasite therapeutics.
                     J. Biol. Chem.,  1998, 273(41), 26497-26505.
[http://dx.doi.org/10.1074/jbc.273.41.26497] [PMID: 9756885] 
[18] 
Ali, B.R.; Pal, A.; Croft, S.L.; Taylor, R.J.; Field, M.C. The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a complex mode of action including major effects on mitochondria. Mol. Biochem. Parasitol.,  1999, 104(1), 67-80.
[http://dx.doi.org/10.1016/S0166-6851(99)00131-0] [PMID: 10589982] 
[19] 
Miyashita, K.; Imanishi, T. Syntheses of natural products having an epoxyquinone structure. Chem. Rev.,  2005, 105(12), 4515-4536.
[http://dx.doi.org/10.1021/cr040613k] [PMID: 16351052] 
[20] 
Sekizawa, R.; Ikeno, S.; Nakamura, H.; Naganawa, H.; Matsui, S.; Iinuma, H.; Takeuchi, T. Panepophenanthrin, from a mushroom strain, a novel inhibitor of the ubiquitin-activating enzyme. J. Nat. Prod.,  2002, 65(10), 1491-1493.
[http://dx.doi.org/10.1021/np020098q] [PMID: 12398550] 
[21] 
Kamiyama, H.; Usui, T.; Uramoto, M.; Takagi, H.; Shoji, M.; Hayashi, Y.; Kakeya, H.; Osada, H. Fungal metabolite, epoxyquinol B, crosslinks proteins by epoxy-thiol conjugation. J. Antibiot. (Tokyo),  2008, 61(2), 94-97.
[http://dx.doi.org/10.1038/ja.2008.117] [PMID: 18408330] 
[22] 
Koizumi, F.; Ishiguro, H.; Ando, K.; Kondo, H.; Yoshida, M.; Matsuda, Y.; Nakanishi, S. EI-1941-1 and -2, novel interleukin-1 beta converting enzyme inhibitors Produced by Farrowia sp. E-1941. II. Taxonomy of producing strain, fermentation, isolation, physico-chemical properties, and biological properties. J. Antibiot. (Tokyo),  2003, 56(7), 603-609.
[http://dx.doi.org/10.7164/antibiotics.56.603] [PMID: 14513902] 
[23] 
Singh, S.B.; Zink, D.L.; Liesch, J.M.; Ball, R.G.; Goetz, M.A.; Bolessa, E.A.; Giacobbe, R.A.; Silverman, K.C.; Bills, G.F. Preussomerins and deoxypreussomerins: novel inhibitors of Ras farnesyl-protein transferase. J. Org. Chem.,  1994, 59(21), 6296-6302.
[http://dx.doi.org/10.1021/jo00100a035] 
[24] 
Nakashima, T.; Tanaka, R.; Yamashita, Y.; Kanda, Y.; Hara, M. Aranorosin and a novel derivative inhibit the anti-apoptotic functions regulated by Bcl-2. Biochem. Biophys. Res. Commun.,  2008, 377(4), 1085-1090.
[http://dx.doi.org/10.1016/j.bbrc.2008.10.112] [PMID: 18977202] 
[25] 
Herath, K.B.; Jayasuriya, H.; Bills, G.F.; Polishook, J.D.; Dombrowski, A.W.; Guan, Z.; Felock, P.J.; Hazuda, D.J.; Singh, S.B. Isolation, structure, absolute stereochemistry, and HIV-1 integrase inhibitory activity of integrasone, a novel fungal polyketide. J. Nat. Prod.,  2004, 67(5), 872-874.
[http://dx.doi.org/10.1021/np0340504] [PMID: 15165153] 
[26] 
Sattler, I.; Thiericke, R.; Zeeck, A. The manumycin-group metabolites. Nat. Prod. Rep.,  1998, 15(3), 221-240.
[http://dx.doi.org/10.1039/a815221y] [PMID: 9652122] 
[27] 
Taylor, R.J.K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.; Wei, X.; Lewis, N. The synthesis of alisamycin, nisamycin, LL-C10037α and novel epoxyquinol and epoxyquinone analogues of manumycin A. Synthesis (Stuttg),  1998, 1998, 775-790.
[http://dx.doi.org/10.1055/s-1998-2064] 
[28] 
Zilbeyaz, K.; Sahin, E.; Kilic, H. 
                        Synthesis of enantiomerically pure analogues of the 
                        
                            meta
                        
                        -substituted aniline antibiotics.
                     Tetrahed.: Asymm.,  2007, 18(6), 791-796.
[http://dx.doi.org/10.1016/j.tetasy.2007.03.003] 
[29] 
Wipf, P.; Coish, P.D.G. Organozirconocene-mediated polyene synthesis: preparation of asukamycin and manumycin a side chains. Tetrahedron Lett.,  1997, 38(29), 5073-5076.
[http://dx.doi.org/10.1016/S0040-4039(97)01129-5] 
[30] 
Hara, M.; Akasaka, K.; Akinaga, S.; Okabe, M.; Nakano, H.; Gomez, R.; Wood, D.; Uh, M.; Tamanoi, F. Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc. Natl. Acad. Sci. USA,  1993, 90(6), 2281-2285.
[http://dx.doi.org/10.1073/pnas.90.6.2281] [PMID: 8460134] 
[31] 
Sugita, M.; Sugita, H.; Kaneki, M. Farnesyltransferase inhibitor, manumycin a, prevents atherosclerosis development and reduces oxidative stress in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol.,  2007, 27(6), 1390-1395.
[http://dx.doi.org/10.1161/ATVBAHA.107.140673] [PMID: 17363690] 
[32] 
Bernier, M.; Kwon, Y-K.; Pandey, S.K.; Zhu, T-N.; Zhao, R-J.; Maciuk, A.; He, H-J.; Decabo, R.; Kole, S. Binding of manumycin A inhibits IkappaB kinase β activity. J. Biol. Chem.,  2006, 281(5), 2551-2561.
[http://dx.doi.org/10.1074/jbc.M511878200] [PMID: 16319058] 
[33] 
Zheng, Z-H.; Dong, Y-S.; Zhang, H.; Lu, X-H.; Ren, X.; Zhao, G.; He, J-G.; Si, S-Y. Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain. J. Enzyme Inhib. Med. Chem.,  2007, 22(1), 43-49.
[http://dx.doi.org/10.1080/14756360600988781] [PMID: 17373546] 
[34] 
Tanaka, T.; Tsukuda, E.; Uosaki, Y.; Matsuda, Y. 
                        EI-1511-3, -5 and EI-1625-2, novel interleukin-1 beta converting enzyme inhibitors produced by 
                        
                            Streptomyces
                        
                         sp. E-1511 and E-1625. III. Biochemical properties of EI-1511-3, -5 and EI-1625-2.
                     J. Antibiot. (Tokyo),  1996, 49(11), 1085-1090.
[http://dx.doi.org/10.7164/antibiotics.49.1085] [PMID: 8982335] 
[35] 
Zeeck, A.; Frobel, K.; Heusel, C.; Schröder, K.; Thiericke, R. The structure of manumycin. II. Derivatives. J. Antibiot. (Tokyo),  1987, 40(11), 1541-1548.
[http://dx.doi.org/10.7164/antibiotics.40.1541] [PMID: 3693124] 
[36] 
Ito, T.; Kawata, S.; Tamura, S.; Igura, T.; Nagase, T.; Miyagawa, J.I.; Yamazaki, E.; Ishiguro, H.; Matasuzawa, Y. Suppression of human pancreatic cancer growth in BALB/c nude mice by manumycin, a farnesyl:protein transferase inhibitor. Jpn. J. Cancer Res.,  1996, 87(2), 113-116.
[http://dx.doi.org/10.1111/j.1349-7006.1996.tb03146.x] [PMID: 8609057] 
[37] 
Kapiteijn, E.; Schneider, T.C.; Morreau, H.; Gelderblom, H.; Nortier, J.W.R.; Smit, J.W.A. New treatment modalities in advanced thyroid cancer. Ann. Oncol.,  2012, 23(1), 10-18.
[http://dx.doi.org/10.1093/annonc/mdr117] [PMID: 21471561] 
[38] 
Yeung, S.C.; Xu, G.; Pan, J.; Christgen, M.; Bamiagis, A. Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells. Cancer Res.,  2000, 60(3), 650-656.
[PMID: 10676649] 
[39] 
Kainuma, O.; Asano, T.; Hasegawa, M.; Kenmochi, T.; Nakagohri, T.; Tokoro, Y.; Isono, K. Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin. Pancreas,  1997, 15(4), 379-383.
[http://dx.doi.org/10.1097/00006676-199711000-00008] [PMID: 9361092] 
[40] 
Di Paolo, A.; Danesi, R.; Nardini, D.; Bocci, G.; Innocenti, F.; Fogli, S.; Barachini, S.; Marchetti, A.; Bevilacqua, G.; Del Tacca, M. Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumour cells. Br. J. Cancer,  2000, 82(4), 905-912.
[http://dx.doi.org/10.1054/bjoc.1999.1018] [PMID: 10732765] 
[41] 
Nagase, T.; Kawata, S.; Tamura, S.; Matsuda, Y.; Inui, Y.; Yamasaki, E.; Ishiguro, H.; Ito, T.; Matsuzawa, Y. Inhibition of cell growth of human hepatoma cell line (Hep G2) by a farnesyl protein transferase inhibitor: a preferential suppression of ras farnesylation. Int. J. Cancer,  1996, 65(5), 620-626.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19960301)65:5<620::AID-IJC11>3.0.CO;2-B] [PMID: 8598313] 
[42] 
Sinn, E.; Muller, W.; Pattengale, P.; Tepler, I.; Wallace, R.; Leder, P. 
                        Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes 
                        
                            in vivo
                        
                    .
                     Cell,  1987, 49(4), 465-475.
[http://dx.doi.org/10.1016/0092-8674(87)90449-1] [PMID: 3032456] 
[43] 
Mangues, R.; Seidman, I.; Pellicer, A.; Gordon, J.W. Tumorigenesis and male sterility in transgenic mice expressing a MMTV/N-ras oncogene. Oncogene,  1990, 5(10), 1491-1497.
[PMID: 2174525] 
[44] 
Lantry, L.E.; Zhang, Z.; Crist, K.A.; Wang, Y.; Hara, M.; Zeeck, A.; Lubet, R.A.; You, M. Chemopreventive efficacy of promising farnesyltransferase inhibitors. Exp. Lung Res.,  2000, 26(8), 773-790.
[http://dx.doi.org/10.1080/01902140150216819] [PMID: 11195470] 
[45] 
Bos, J.L. ras oncogenes in human cancer: a review. Cancer Res.,  1989, 49(17), 4682-4689.
[PMID: 2547513] 
[46] 
Marshall, C.J. Protein prenylation: a mediator of protein-protein interactions. Science,  1993, 259(5103), 1865-1866.
[http://dx.doi.org/10.1126/science.8456312] [PMID: 8456312] 
[47] 
Danesi, R.; Nardini, D.; Basolo, F.; Del Tacca, M.; Samid, D.; Myers, C.E. Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene. Mol. Pharmacol.,  1996, 49(6), 972-979.
[PMID: 8649357] 
[48] 
Larcher, F.; Robles, A.I.; Duran, H.; Murillas, R.; Quintanilla, M.; Cano, A.; Conti, C.J.; Jorcano, J.L. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res.,  1996, 56(23), 5391-5396.
[PMID: 8968091] 
[49] 
Rodenhuis, S.; Boerrigter, L.; Top, B.; Slebos, R.J.; Mooi, W.J.; van’t Veer, L.; van Zandwijk, N. Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study. J. Clin. Oncol.,  1997, 15(1), 285-291.
[http://dx.doi.org/10.1200/JCO.1997.15.1.285] [PMID: 8996154] 
[50] 
Shih, T.Y.; Papageorge, A.G.; Stokes, P.E.; Weeks, M.O.; Scolnick, E.M. Guanine nucleotide-binding and autophosphorylating activities associated with the p21src protein of Harvey murine sarcoma virus. Nature,  1980, 287(5784), 686-691.
[http://dx.doi.org/10.1038/287686a0] [PMID: 6253810] 
[51] 
Chardin, P.; Camonis, J.H.; Gale, N.W.; van Aelst, L.; Schlessinger, J.; Wigler, M.H.; Bar-Sagi, D. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science,  1993, 260(5112), 1338-1343.
[http://dx.doi.org/10.1126/science.8493579] [PMID: 8493579] 
[52] 
Bollag, G.; McCormick, F. GTPase activating proteins. Semin. Cancer Biol.,  1992, 3(4), 199-208.
[PMID: 1421164] 
[53] 
Willingham, M.C.; Pastan, I.; Shih, T.Y.; Scolnick, E.M. Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell,  1980, 19(4), 1005-1014.
[http://dx.doi.org/10.1016/0092-8674(80)90091-4] [PMID: 6247068] 
[54] 
Hancock, J.F.; Magee, A.I.; Childs, J.E.; Marshall, C.J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell,  1989, 57(7), 1167-1177.
[http://dx.doi.org/10.1016/0092-8674(89)90054-8] [PMID: 2661017] 
[55] 
Der, C.J.; Cox, A.D. Isoprenoid modification and plasma membrane association: critical factors for ras oncogenicity. Cancer Cells,  1991, 3(9), 331-340.
[PMID: 1751286] 
[56] 
Gibbs, J.B.; Oliff, A. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu. Rev. Pharmacol. Toxicol.,  1997, 37, 143-166.
[http://dx.doi.org/10.1146/annurev.pharmtox.37.1.143] [PMID: 9131250] 
[57] 
Cox, A.D.; Der, C.J. Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim. Biophys. Acta,  1997, 1333(1), F51-F71.
[http://dx.doi.org/10.1016/s0304-419x(97)00011-5] [PMID: 9294018] 
[58] 
Maltese, W.A. Posttranslational modification of proteins by isoprenoids in mammalian cells. FASEB J.,  1990, 4(15), 3319-3328.
[http://dx.doi.org/10.1096/fasebj.4.15.2123808] [PMID: 2123808] 
[59] 
Cox, A.D.; Der, C.J. Protein prenylation: more than just glue? Curr. Opin. Cell Biol.,  1992, 4(6), 1008-1016.
[http://dx.doi.org/10.1016/0955-0674(92)90133-W] [PMID: 1485954] 
[60] 
Gibbs, J.B.; Oliff, A.; Kohl, N.E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell,  1994, 77(2), 175-178.
[http://dx.doi.org/10.1016/0092-8674(94)90308-5] [PMID: 8168127] 
[61] 
Kato, K.; Cox, A.D.; Hisaka, M.M.; Graham, S.M.; Buss, J.E.; Der, C.J. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc. Natl. Acad. Sci. USA,  1992, 89(14), 6403-6407.
[http://dx.doi.org/10.1073/pnas.89.14.6403] [PMID: 1631135] 
[62] 
Clarke, S. Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu. Rev. Biochem.,  1992, 61, 355-386.
[http://dx.doi.org/10.1146/annurev.bi.61.070192.002035] [PMID: 1497315] 
[63] 
Zhang, F.L.; Casey, P.J. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem.,  1996, 65, 241-269.
[http://dx.doi.org/10.1146/annurev.bi.65.070196.001325] [PMID: 8811180] 
[64] 
Chen, W-J.; Andres, D.A.; Goldstein, J.L.; Russell, D.W.; Brown, M.S. cDNA cloning and expression of the peptide-binding β subunit of rat p21ras farnesyltransferase, the counterpart of yeast DPR1/RAM1. Cell,  1991, 66(2), 327-334.
[http://dx.doi.org/10.1016/0092-8674(91)90622-6] [PMID: 1855253] 
[65] 
Omer, C.A.; Kral, A.M.; Diehl, R.E.; Prendergast, G.C.; Powers, S.; Allen, C.M.; Gibbs, J.B.; Kohl, N.E. Characterization of recombinant human farnesyl-protein transferase: cloning, expression, farnesyl diphosphate binding, and functional homology with yeast prenyl-protein transferases. Biochemistry,  1993, 32(19), 5167-5176.
[http://dx.doi.org/10.1021/bi00070a028] [PMID: 8494894] 
[66] 
Qian, D.; Zhou, D.; Ju, R.; Cramer, C.L.; Yang, Z. Protein farnesyltransferase in plants: molecular characterization and involvement in cell cycle control. Plant Cell,  1996, 8(12), 2381-2394.
[http://dx.doi.org/10.1105/tpc.8.12.2381] [PMID: 8989889] 
[67] 
Chen, W.J.; Moomaw, J.F.; Overton, L.; Kost, T.A.; Casey, P.J. High level expression of mammalian protein farnesyltransferase in a baculovirus system. The purified protein contains zinc. J. Biol. Chem.,  1993, 268(13), 9675-9680.
[http://dx.doi.org/10.1016/S0021-9258(18)98402-4] [PMID: 8486655] 
[68] 
Schafer, W.R.; Kim, R.; Sterne, R.; Thorner, J.; Kim, S.H.; Rine, J. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science,  1989, 245(4916), 379-385.
[http://dx.doi.org/10.1126/science.2569235] [PMID: 2569235] 
[69] 
Manne, V.; Roberts, D.; Tobin, A.; O’Rourke, E.; De Virgilio, M.; Meyers, C.; Ahmed, N.; Kurz, B.; Resh, M.; Kung, H.F. Identification and preliminary characterization of protein-cysteine farnesyltransferase. Proc. Natl. Acad. Sci. USA,  1990, 87(19), 7541-7545.
[http://dx.doi.org/10.1073/pnas.87.19.7541] [PMID: 2217184] 
[70] 
Reiss, Y.; Goldstein, J.L.; Seabra, M.C.; Casey, P.J.; Brown, M.S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell,  1990, 62(1), 81-88.
[http://dx.doi.org/10.1016/0092-8674(90)90242-7] [PMID: 2194674] 
[71] 
Schaber, M.D.; O’Hara, M.B.; Garsky, V.M.; Mosser, S.C.; Bergstrom, J.D.; Moores, S.L.; Marshall, M.S.; Friedman, P.A.; Dixon, R.A.; Gibbs, J.B. Polyisoprenylation of Ras in vitro by a farnesyl-protein transferase. J. Biol. Chem.,  1990, 265(25), 14701-14704.
[http://dx.doi.org/10.1016/S0021-9258(18)77164-0] [PMID: 2203759] 
[72] 
Goldstein, J.L.; Brown, M.S. Regulation of the mevalonate pathway. Nature,  1990, 343(6257), 425-430.
[http://dx.doi.org/10.1038/343425a0] [PMID: 1967820] 
[73] 
Moores, S.L.; Schaber, M.D.; Mosser, S.D.; Rands, E.; O’Hara, M.B.; Garsky, V.M.; Marshall, M.S.; Pompliano, D.L.; Gibbs, J.B. Sequence dependence of protein isoprenylation. J. Biol. Chem.,  1991, 266(22), 14603-14610.
[http://dx.doi.org/10.1016/S0021-9258(18)98729-6] [PMID: 1860864] 
[74] 
James, G.; Goldstein, J.L.; Brown, M.S. Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc. Natl. Acad. Sci. USA,  1996, 93(9), 4454-4458.
[http://dx.doi.org/10.1073/pnas.93.9.4454] [PMID: 8633088] 
[75] 
Whyte, D.B.; Kirschmeier, P.; Hockenberry, T.N.; Nunez-Oliva, I.; James, L.; Catino, J.J.; Bishop, W.R.; Pai, J-K. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem.,  1997, 272(22), 14459-14464.
[http://dx.doi.org/10.1074/jbc.272.22.14459] [PMID: 9162087] 
[76] 
Zhang, F.L.; Kirschmeier, P.; Carr, D.; James, L.; Bond, R.W.; Wang, L.; Patton, R.; Windsor, W.T.; Syto, R.; Zhang, R.; Bishop, W.R. 
                        Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as 
                        
                            in vitro
                        
                         substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I.
                     J. Biol. Chem.,  1997, 272(15), 10232-10239.
[http://dx.doi.org/10.1074/jbc.272.15.10232] [PMID: 9092572] 
[77] 
Cox, A.D.; Hisaka, M.M.; Buss, J.E.; Der, C.J. Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein. Mol. Cell. Biol.,  1992, 12(6), 2606-2615.
[http://dx.doi.org/10.1128/MCB.12.6.2606] [PMID: 1375323] 
[78] 
Sun, J.; Qian, Y.; Hamilton, A.D.; Sebti, S.M. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene,  1998, 16(11), 1467-1473.
[http://dx.doi.org/10.1038/sj.onc.1201656] [PMID: 9525745] 
[79] 
Buzzetti, F.; Gaeumann, E.; Huetter, R.; Keller-Schierlein, W.; Neipp, L.; Prelog, V.; Zaehner, H. [METABOLITES OF MICROORGANISMS. 41. MANUMYCIN Pharm. Acta Helv.,  1963, 38, 871-874. [Metabolites of microorganisms. 41. Manumycin
[PMID: 14208615] 
[80] 
Cho, H.; Sattler, I.; Beale, J.M.; Zeeck, A.; Floss, H.G. Some Aspects of the Stereochemistry and Biosynthesis of Asukamycin. J. Org. Chem.,  1993, 58(27), 7925-7928.
[http://dx.doi.org/10.1021/jo00079a047] 
[81] 
Omura, S.; Kitao, C.; Tanaka, H.; Oiwa, R.; Takahashi, Y. 
                        A new antibiotic, asukamycin, produced by 
                        
                            Streptomyces
                        
                    .
                     J. Antibiot. (Tokyo),  1976, 29(9), 876-881.
[http://dx.doi.org/10.7164/antibiotics.29.876] [PMID: 993129] 
[82] 
Chatterjee, S.; Vijayakumar, E.K.; Franco, C.M.; Blumbach, J.; Ganguli, B.N.; Fehlhaber, H.W.; Kogler, H. On the structure of alisamycin, a new member of the manumycin class of antibiotics. J. Antibiot. (Tokyo),  1993, 46(6), 1027-1030.
[http://dx.doi.org/10.7164/antibiotics.46.1027] [PMID: 8344865] 
[83] 
Macdonald, G.; Alcaraz, L.; Lewis, N.J.; Taylor, R.J. 
                        Asymmetric synthesis of the 
                        
                            m
                        
                        C7N core of the manumycin family: preparation of (+)-MT 35214 and a formal total synthesis of (−)-Alisamycin.
                     Tetrahedron Lett.,  1998, 39(30), 5433-5436.
[http://dx.doi.org/10.1016/S0040-4039(98)01047-8] 
[84] 
Hayashi, K.; Nakagawa, M.; Fujita, T.; Tanimori, S.; Nakayama, M. 
                        Nisamycin, a new manumycin group antibiotic from S
                        
                            treptomyces 
                        
                        sp. K106.
                     J. Antibiot. (Tokyo),  1993, 46(12), 1904-1907.
[http://dx.doi.org/10.7164/antibiotics.46.1904] [PMID: 8294252] 
[85] 
Sattler, I.; Groene, C.; Zeeck, A. New compounds of the manumycin group of antibiotics and a facilitated route for their structure elucidation. J. Org. Chem.,  1993, 58(24), 6583-6587.
[http://dx.doi.org/10.1021/jo00076a015] 
[86] 
Thiericke, R.; Zeeck, A.; Nakagawa, A.; Omura, S.; Herrold, R.E.; Wu, S.T.S.; Beale, J.M.; Floss, H.G. Biosynthesis of the Manumycin Group Antibiotics. J. Am. Chem. Soc.,  1990, 112(10), 3979-3987.
[http://dx.doi.org/10.1021/ja00166a039] 
[87] 
Shu, Y.Z.; Huang, S.; Wang, R.R.; Lam, K.S.; Klohr, S.E.; Volk, K.J.; Pirnik, D.M.; Wells, J.S.; Fernandes, P.B.; Patel, P.S.; Manumycins, E. Manumycins E, F and G, new members of manumycin class antibiotics, from Streptomyces sp. J. Antibiot. (Tokyo),  1994, 47(3), 324-333.
[http://dx.doi.org/10.7164/antibiotics.47.324] [PMID: 8175485] 
[88] 
Slechta, L.; Cialdella, J.I.; Mizsak, S.A.; Hoeksema, H. Isolation and characterization of a new antibiotic U-62162. J. Antibiot. (Tokyo),  1982, 35(5), 556-560.
[http://dx.doi.org/10.7164/antibiotics.35.556] [PMID: 7107520] 
[89] 
Uosaki, Y.; Agatsuma, T.; Tanaka, T.; Saitoh, Y. EI-1511-3, -5 and EI-1625-2, novel interleukin-1 beta converting enzyme inhibitors produced by Streptomyces sp. E-1511 and E-1625. II. Structure determination. J. Antibiot. (Tokyo),  1996, 49(11), 1079-1084.
[http://dx.doi.org/10.7164/antibiotics.49.1079] [PMID: 8982334] 
[90] 
Gautier, E.C.L.; Lewis, N.J.; McKillop, A.; Taylor, R.J.K. Synthesis of bromoxone. Tetrahedron Lett.,  1994, 35(47), 8759-8760.
[http://dx.doi.org/10.1016/S0040-4039(00)78490-5] 
[91] 
Wipf, P.; Kim, Y. Synthesis of the antitumor antibiotic LL-C10037.alpha. J. Org. Chem.,  1994, 59(13), 3518-3519.
[http://dx.doi.org/10.1021/jo00092a004] 
[92] 
Kapfer, I.; Lewis, N.J.; Macdonald, G.; Taylor, R.J.K. The synthesis of novel analogues of the manumycin family of antibiotics and the antitumour antibiotic LL-C10037α. Tetrahedron Lett.,  1996, 37(12), 2101-2104.
[http://dx.doi.org/10.1016/0040-4039(96)00203-1] 
[93] 
Box, S.J.; Gilpin, M.L.; Gwynn, M.; Hanscomb, G.; Spear, S.R.; Brown, A.G. 
                        MM 14201, a new epoxyquinone derivative with antibacterial activity produced by a species of 
                        
                            Streptomyces.
                         J. Antibiot. (Tokyo),  1983, 36(12), 1631-1637.
[http://dx.doi.org/10.7164/antibiotics.36.1631] [PMID: 6363372] 
[94] 
Lee, M.D.; Fantini, A.A.; Morton, G.O.; James, J.C.; Borders, D.B.; Testa, R.T. New antitumor antibiotic, LL-C10037 alpha. Fermentation, isolation and structure determination. J. Antibiot. (Tokyo),  1984, 37(10), 1149-1152.
[http://dx.doi.org/10.7164/antibiotics.37.1149] [PMID: 6548735] 
[95] 
Kohno, J.; Nishio, M.; Kawano, K.; Nakanishi, N.; Suzuki, S.; Uchida, T.; Komatsubara, S. 
                        TMC-1 A, B, C and D, new antibiotics of the manumycin group produced by 
                        
                            Streptomyces
                        
                         sp. Taxonomy, production, isolation, physico-chemical properties, structure elucidation and biological properties.
                     J. Antibiot. (Tokyo),  1996, 49(12), 1212-1220.
[http://dx.doi.org/10.7164/antibiotics.49.1212] [PMID: 9031666] 
[96] 
Hayashi, K.; Nakagawa, M.; Fujita, T.; Nakayama, M. Absolute Stereochemistry of Alisamycin. Biosci. Biotechnol. Biochem.,  1994, 58(7), 1332-1333.
[http://dx.doi.org/10.1271/bbb.58.1332] 
[97] 
Brodasky, T.F.; Stroman, D.W.; Dietz, A.; Mizsak, S. U-56,407, a new antibiotic related to asukamycin: isolation and characterization. J. Antibiot. (Tokyo),  1983, 36(8), 950-956.
[http://dx.doi.org/10.7164/antibiotics.36.950] [PMID: 6630064] 
[98] 
Tamanoi, F. 207th ACS national meeting. Anal. Chem.,  1994, 66(5), 312A-317A.
[http://dx.doi.org/10.1021/ac00077a728] 
[99] 
Wipf, P.; Xu, W.; Takahashi, H.; Jahn, H.; Coish, P.D.G. Synthetic applications of organozirconocenes. Pure Appl. Chem.,  1997, 69(3), 639-644.
[http://dx.doi.org/10.1351/pac199769030639] 
[100] 
Alcaraz, L.; Macdonald, G.; Ragot, J.; Lewis, N.J.; Taylor, R.J.K. Synthetic Approaches to the manumycin A, B and C antibiotics: the first total synthesis of (+)-manumycin A. Tetrahedron,  1999, 55(12), 3707-3716.
[http://dx.doi.org/10.1016/S0040-4020(98)00879-5] 
[101] 
Hara, M.; Han, M. 
                        Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in 
                        
                            Caenorhabditis elegans
                        
                    .
                     Proc. Natl. Acad. Sci. USA,  1995, 92(8), 3333-3337.
[http://dx.doi.org/10.1073/pnas.92.8.3333] [PMID: 7536929] 
[102] 
Kapfer, I.; Lewis, N.J. Macdonald, Gregor, Taylor, R.J.K. The synthesis of novel analogues of the manumycin family of antibiotics and the antitumour antibiotic LL-C10037α. Tetrahedron Lett.,  1996, 37(12), 2101-2104.
[http://dx.doi.org/10.1016/0040-4039(96)00203-1] 
[103] 
Rui, Z.; Sandy, M.; Jung, B.; Zhang, W. Tandem enzymatic oxygenations in biosynthesis of epoxyquinone pharmacophore of manumycin-type metabolites. Chem. Biol.,  2013, 20(7), 879-887.
[http://dx.doi.org/10.1016/j.chembiol.2013.05.006] [PMID: 23890006] 
[104] 
Gonzales, J.; Jim Yeung, S.C.; Smith, J.A. High-performance liquid chromatographic assay validation of Manumycin A in mouse plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.,  2002, 776(2), 177-182.
[http://dx.doi.org/10.1016/S1570-0232(02)00334-3] [PMID: 12137999] 
[105] 
Yang, W.; Del Villar, K.; Urano, J.; Mitsuzawa, H.; Tamanoi, F. Advances in the development of farnesyltransferase inhibitors: substrate recognition by protein farnesyltransferase. J. Cell. Biochem. Suppl.,  1997, 27, 12-19.
[http://dx.doi.org/10.1002/(SICI)1097-4644(1997)27+<12::AID-JCB5>3.0.CO;2-4] [PMID: 9591188] 
[106] 
Shen, B.; Whittle, Y.G.; Gould, S.J.; Keszler, D.A. 
                        Structure and absolute stereochemistry of the epoxyquinol LL-C10037.alpha. and related metabolites from 
                        
                            Streptomyces
                        
                         LL-C10037.
                     J. Org. Chem.,  1990, 55(14), 4422-4426.
[http://dx.doi.org/10.1021/jo00301a039] 
[107] 
Gould, S.J.; Kirchmeier, M.J.; LaFever, R.E. Incorporation of two oxygens from 18O2 in the epoxyquinone from the dihydroxyacetanilide epoxidase reaction: evidence for a dioxygenase mechanism. J. Am. Chem. Soc.,  1996, 118(33), 7663-7666.
[http://dx.doi.org/10.1021/ja960696p] 
[108] 
Whittle, Y.G.; Gould, S.J. The biosynthesis of LL-C10037.alpha. from the shikimate pathway. J. Am. Chem. Soc.,  1987, 109(16), 5043-5044.
[http://dx.doi.org/10.1021/ja00250a057] 
[109] 
Cronjé Grové, J.J.; Wei, X.; Taylor, R.J.K. The first total synthesis of a type II manumycin antibiotic, (+)-TMC-1 A: the total syntheses of (−)-LL-C10037β and (+)-manumycin B. Chem. Commun. (Camb.),  1999, (5), 421-422.
[http://dx.doi.org/10.1039/a900261h] 
[110] 
Murphy, S.T.; Bencsik, J.R.; Johnson, C.R. Enantioselective synthesis of (−)-LL-C10037α from benzoquinone. Org. Lett.,  1999, 1(9), 1483-1485.
[http://dx.doi.org/10.1021/ol991038n] 
[111] 
Isobe, Y.; Okumura, M.; McGregor, L.M.; Brittain, S.M.; Jones, M.D.; Liang, X.; White, R.; Forrester, W.; McKenna, J.M.; Tallarico, J.A.; Schirle, M.; Maimone, T.J.; Nomura, D.K. Manumycin polyketides act as molecular glues between UBR7 and P53. Nat. Chem. Biol.,  2020, 16(11), 1189-1198.
[http://dx.doi.org/10.1038/s41589-020-0557-2] [PMID: 32572277] 
[112] 
Sačková, V.; Fedoročko, P. Anticancer activities of natural farnesyltransferase inhibitor manumycin A. In: The Research and Biology of Cancer I, 1st Edition; iConcept Press Ltd, 2013; pp. 1-20.
[113] 
Shipley, P.R.; Donnelly, C.C.; Le, C.H.; Bernauer, A.D.; Klegeris, A. 
                        Antitumor activity of asukamycin, a secondary metabolite from the actinomycete bacterium 
                        
                            Streptomyces nodosus
                        
                         subspecies asukaensis.
                     Int. J. Mol. Med.,  2009, 24(5), 711-715.
[http://dx.doi.org/10.3892/ijmm_00000283] [PMID: 19787206] 
[114] 
Xu, G.; Pan, J.; Martin, C.; Yeung, S.C. Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma. J. Clin. Endocrinol. Metab.,  2001, 86(4), 1769-1777.
[http://dx.doi.org/10.1210/jc.86.4.1769] [PMID: 11297616] 
[115] 
Di Paolo, A.; Danesi, R.; Caputo, S.; Macchia, M.; Lastella, M.; Boggi, U.; Mosca, F.; Marchetti, A.; Del Tacca, M. Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells. Br. J. Cancer,  2001, 84(11), 1535-1543.
[http://dx.doi.org/10.1054/bjoc.2001.1820] [PMID: 11384105] 
[116] 
Karp, J.E. Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies. Semin. Hematol.,  2001, 38(3)(Suppl. 7), 16-23.
[http://dx.doi.org/10.1053/shem.2001.27482] [PMID: 11523024] 
[117] 
Kurzrock, R.; Cortes, J.; Kantarjian, H. Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome. Semin. Hematol.,  2002, 39(4)(Suppl. 3), 20-24.
[http://dx.doi.org/10.1053/shem.2002.36925] [PMID: 12447848] 
[118] 
Selleri, C.; Maciejewski, J.P.; Montuori, N.; Ricci, P.; Visconte, V.; Serio, B.; Luciano, L.; Rotoli, B. Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells. Blood,  2003, 102(4), 1490-1498.
[http://dx.doi.org/10.1182/blood-2003-01-0178] [PMID: 12714496] 
[119] 
Liu, L.; Taverna, P.; Whitacre, C.M.; Chatterjee, S.; Gerson, S.L. Pharmacologic disruption of base excision repair sensitizes mismatch repair-deficient and -proficient colon cancer cells to methylating agents. Clin. Cancer Res.,  1999, 5(10), 2908-2917.
[PMID: 10537360] 
[120] 
Liu, L.; Nakatsuru, Y.; Gerson, S.L. Base excision repair as a therapeutic target in colon cancer. Clin. Cancer Res.,  2002, 8(9), 2985-2991.
[PMID: 12231545] 
[121] 
Taverna, P.; Hwang, H-S.; Schupp, J.E.; Radivoyevitch, T.; Session, N.N.; Reddy, G.; Zarling, D.A.; Kinsella, T.J. Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization. Cancer Res.,  2003, 63(4), 838-846.
[PMID: 12591735] 
[122] 
Zeeck, A.; Schröder, K.; Frobel, K.; Grote, R.; Thiericke, R. The structure of manumycin. I. Characterization, structure elucidation and biological activity. J. Antibiot. (Tokyo),  1987, 40(11), 1530-1540.
[http://dx.doi.org/10.7164/antibiotics.40.1530] [PMID: 3693123] 
[123] 
She, M.; Pan, I.; Sun, L.; Yeung, S-C.J. Enhancement of manumycin A-induced apoptosis by methoxyamine in myeloid leukemia cells. Leukemia,  2005, 19(4), 595-602.
[http://dx.doi.org/10.1038/sj.leu.2403691] [PMID: 15744347] 
[124] 
Cabot, R.C.; Mallory, T.B. Case 27461. N. Engl. J. Med.,  1941, 225, 789-791.
[http://dx.doi.org/10.1056/NEJM194111132252007] 
[125] 
Donovan, P.J.; Achong, N.; Griffin, K.; Galligan, J.; Pretorius, C.J.; McLeod, D.S.A. PTHrP-mediated hypercalcemia: causes and survival in 138 patients. J. Clin. Endocrinol. Metab.,  2015, 100(5), 2024-2029.
[http://dx.doi.org/10.1210/jc.2014-4250] [PMID: 25719931] 
[126] 
Mirrakhimov, A.E. Hypercalcemia of malignancy: an update on pathogenesis and management. N. Am. J. Med. Sci.,  2015, 7(11), 483-493.
[http://dx.doi.org/10.4103/1947-2714.170600] [PMID: 26713296] 
[127] 
Henderson, J.E.; Amizuka, N.; Warshawsky, H.; Biasotto, D.; Lanske, B.M.; Goltzman, D.; Karaplis, A.C. Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol. Cell. Biol.,  1995, 15(8), 4064-4075.
[http://dx.doi.org/10.1128/MCB.15.8.4064] [PMID: 7623802] 
[128] 
Motokura, T.; Endo, K.; Kumaki, K.; Ogata, E.; Ikeda, K. Neoplastic transformation of normal rat embryo fibroblasts by a mutated p53 and an activated ras oncogene induces parathyroid hormone-related peptide gene expression and causes hypercalcemia in nude mice. J. Biol. Chem.,  1995, 270(52), 30857-30861.
[http://dx.doi.org/10.1074/jbc.270.52.30857] [PMID: 8537338] 
[129] 
Rabbani, S.A.; Gladu, J.; Liu, B.; Goltzman, D. 
                        Regulation
                        
                             in vivo
                        
                         of the growth of Leydig cell tumors by antisense ribonucleic acid for parathyroid hormone-related peptide.
                     Endocrinology,  1995, 136(12), 5416-5422.
[http://dx.doi.org/10.1210/endo.136.12.7588290] [PMID: 7588290] 
[130] 
Akino, K.; Ohtsuru, A.; Yano, H.; Ozeki, S.; Namba, H.; Nakashima, M.; Ito, M.; Matsumoto, T.; Yamashita, S. Antisense inhibition of parathyroid hormone-related peptide gene expression reduces malignant pituitary tumor progression and metastases in the rat. Cancer Res.,  1996, 56(1), 77-86.
[PMID: 8548779] 
[131] 
Aklilu, F.; Gladu, J.; Goltzman, D.; Rabbani, S.A. Role of mitogen-activated protein kinases in the induction of parathyroid hormone-related peptide. Cancer Res.,  2000, 60(6), 1753-1760.
[PMID: 10749150] 
[132] 
Aklilu, F.; Park, M.; Goltzman, D.; Rabbani, S.A. Induction of parathyroid hormone-related peptide by the Ras oncogene: role of Ras farnesylation inhibitors as potential therapeutic agents for hypercalcemia of malignancy. Cancer Res.,  1997, 57(20), 4517-4522.
[PMID: 9377563] 
[133] 
She, M.; Yang, H.; Sun, L.; Yeung, S-C.J. Redox control of manumycin A-induced apoptosis in anaplastic thyroid cancer cells: involvement of the xenobiotic apoptotic pathway. Cancer Biol. Ther.,  2006, 5(3), 275-280.
[http://dx.doi.org/10.4161/cbt.5.3.2383] [PMID: 16410725] 
[134] 
Hough, M.A.; Silkstone, G.; Worrall, J.A.R.; Wilson, M.T. NO binding to the proapoptotic cytochrome c-cardiolipin complex. Vitam. Horm.,  2014, 96, 193-209.
[http://dx.doi.org/10.1016/B978-0-12-800254-4.00008-8] [PMID: 25189388] 
[135] 
Dackiw, A.; Pan, J.; Xu, G.; Yeung, S-C.J. Modulation of parathyroid hormone-related protein levels (PTHrP) in anaplastic thyroid cancer. Surgery,  2005, 138(3), 456-463.
[http://dx.doi.org/10.1016/j.surg.2005.06.033] [PMID: 16213899] 
[136] 
Huang, P.; Feng, L.; Oldham, E.A.; Keating, M.J.; Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature,  2000, 407(6802), 390-395.
[http://dx.doi.org/10.1038/35030140] [PMID: 11014196] 
[137] 
Zhou, Y.; Hileman, E.O.; Plunkett, W.; Keating, M.J.; Huang, P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood,  2003, 101(10), 4098-4104.
[http://dx.doi.org/10.1182/blood-2002-08-2512] [PMID: 12531810] 
[138] 
Pelicano, H.; Feng, L.; Zhou, Y.; Carew, J.S.; Hileman, E.O.; Plunkett, W.; Keating, M.J.; Huang, P. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J. Biol. Chem.,  2003, 278(39), 37832-37839.
[http://dx.doi.org/10.1074/jbc.M301546200] [PMID: 12853461] 
[139] 
Schumacker, P.T. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell,  2006, 10(3), 175-176.
[http://dx.doi.org/10.1016/j.ccr.2006.08.015] [PMID: 16959608] 
[140] 
Trachootham, D.; Zhou, Y.; Zhang, H.; Demizu, Y.; Chen, Z.; Pelicano, H.; Chiao, P.J.; Achanta, G.; Arlinghaus, R.B.; Liu, J.; Huang, P. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell,  2006, 10(3), 241-252.
[http://dx.doi.org/10.1016/j.ccr.2006.08.009] [PMID: 16959615] 
[141] 
Pan, J.; She, M.; Xu, Z-X.; Sun, L.; Yeung, S-C.J. 
                        Farnesyltransferase inhibitors induce DNA damage 
                        
                            via
                        
                         reactive oxygen species in human cancer cells.
                     Cancer Res.,  2005, 65(9), 3671-3681.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2744] [PMID: 15867362] 
[142] 
Dixit, D.; Sharma, V.; Ghosh, S.; Koul, N.; Mishra, P.K.; Sen, E. Manumycin inhibits STAT3, telomerase activity, and growth of glioma cells by elevating intracellular reactive oxygen species generation. Free Radic. Biol. Med.,  2009, 47(4), 364-374.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.04.031] [PMID: 19409983] 
[143] 
Singha, P.K.; Pandeswara, S.; Venkatachalam, M.A.; Saikumar, P.; Manumycin, A. Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death. Cell Death Dis.,  2013, 4(1), e457-e457.
[http://dx.doi.org/10.1038/cddis.2012.192] [PMID: 23328664] 
[144] 
Carey, G.B.; Roy, S.K.; Daino, H. The natural tumorcide Manumycin-A targets protein phosphatase 1α and reduces hydrogen peroxide to induce lymphoma apoptosis. Exp. Cell Res.,  2015, 332(1), 136-145.
[http://dx.doi.org/10.1016/j.yexcr.2014.12.009] [PMID: 25556058] 
[145] 
Datta, A.; Kim, H.; Lal, M.; McGee, L.; Johnson, A.; Moustafa, A.A.; Jones, J.C.; Mondal, D.; Ferrer, M.; Abdel-Mageed, A.B.; Manumycin, A. 
                        Manumycin A suppresses exosome biogenesis and secretion 
                        
                            via
                        
                         targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells.
                     Cancer Lett.,  2017, 408, 73-81.
[http://dx.doi.org/10.1016/j.canlet.2017.08.020] [PMID: 28844715] 
[146] 
Ain, K.B. Anaplastic thyroid carcinoma: a therapeutic challenge. Semin. Surg. Oncol.,  1999, 16(1), 64-69.
[http://dx.doi.org/10.1002/(SICI)1098-2388(199901/02)16:1<64::AID-SSU10>3.0.CO;2-U] [PMID: 9890741] 
[147] 
Sweeney, P.J.; Haraf, D.J.; Recant, W.; Kaplan, E.L.; Vokes, E.E. Anaplastic carcinoma of the thyroid. Ann. Oncol.,  1996, 7(7), 739-744.
[http://dx.doi.org/10.1093/oxfordjournals.annonc.a010724] [PMID: 8905033] 
[148] 
Gu, W-Z.; Tahir, S.K.; Wang, Y-C.; Zhang, H-C.; Cherian, S.P.; O’Connor, S.; Leal, J.A.; Rosenberg, S.H.; Ng, S-C. 
                        Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis 
                        
                            in vitro
                        
                         and 
                        
                            in vivo
                        
                    .
                     Eur. J. Cancer,  1999, 35(9), 1394-1401.
[http://dx.doi.org/10.1016/S0959-8049(99)00132-X] [PMID: 10658533] 
[149] 
Feldkamp, M.M.; Lau, N.; Guha, A. Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects. Oncogene,  1999, 18(52), 7514-7526.
[http://dx.doi.org/10.1038/sj.onc.1203105] [PMID: 10602510] 
[150] 
Yang, H-L.; Pan, J-X.; Sun, L.; Yeung, S-C.J. p21 Waf-1 (Cip-1) enhances apoptosis induced by manumycin and paclitaxel in anaplastic thyroid cancer cells. J. Clin. Endocrinol. Metab.,  2003, 88(2), 763-772.
[http://dx.doi.org/10.1210/jc.2002-020992] [PMID: 12574211] 
[151] 
She, M.; Jim Yeung, S-C. Combining a matrix metalloproteinase inhibitor, a farnesyltransferase inhibitor, and a taxane improves survival in an anaplastic thyroid cancer model. Cancer Lett.,  2006, 238(2), 197-201.
[http://dx.doi.org/10.1016/j.canlet.2005.07.012] [PMID: 16154259] 
[152] 
Penjweini, R.; Deville, S.; Ethirajan, A.; Ameloot, M. Investigating the intracellular dynamics of hypericin-loaded nanoparticles and polyvinylpyrrolidone-hypericin by image correlation spectroscopy. In: Nanoscience in Dermatology; Hamblin, M.R.; Prow, T.W.; Avci, P., Eds.; Elsevier, 2016; pp. 275-286.
[http://dx.doi.org/10.1016/B978-0-12-802926-8.00022-7] 
[153] 
Sačková, V.; Kuliková, L.; Kello, M.; Uhrinová, I.; Fedoročko, P. Enhanced antiproliferative and apoptotic response of HT-29 adenocarcinoma cells to combination of photoactivated hypericin and farnesyltransferase inhibitor manumycin A. Int. J. Mol. Sci.,  2011, 12(12), 8388-8405.
[http://dx.doi.org/10.3390/ijms12128388] [PMID: 22272079] 
[154] 
Macejová, M.; Sačková, V.; Hradická, P.; Jendželovský, R.; Demečková, V.; Fedoročko, P. Combination of photoactive hypericin and Manumycin A exerts multiple anticancer effects on oxaliplatin-resistant colorectal cells. Toxicol. In Vitro,  2020, 66, 104860.
[http://dx.doi.org/10.1016/j.tiv.2020.104860] [PMID: 32298799] 
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DOI https://dx.doi.org/10.2174/0929867328666210315123848	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Inhibiting the “Undruggable” RAS/Farnesyltransferase (FTase) Cancer Target by Manumycin-related Natural Products

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