Neste trabalho, a atividade antitumoral e o mecanismo de ação de organometálicos conjugados a íons de Paládio e Rutênio foram avaliados em ensaios pré-clínicos. Os resultados são relevantes para a descoberta de novos agentes antitumorais que, futuramente, poderão ser aplicados na clínica médica.
As principais conclusões do presente trabalho foram:
• O ciclopaladado 7A foi citotóxico in vitro tanto para linhagens celulares tumorais humanas como para a linhagem de melanoma murino B16F10- Nex2. A rápida redução da acidificação extracelular observada após tratamento das células murinas e humanas sugere que o mecanismo de ação desta droga seja semelhante nas células tumorais humanas e murinas;
• O ciclopaladado 7A é efetivo no tratamento do melanoma primário (subcutâneo) e também no tratamento do melanoma metastático experimental. O C7A apresentou baixa toxicidade tanto in vivo como em ensaios in vitro;
• O ciclopaladado 7A tem a mitocôndria como alvo na célula tumoral, catalizando a formação de pontes dissulfeto entre proteínas da membrana mitocondrial, levando à sua agregação. Esse efeito desestabiliza a membrana da mitocôndria, permitindo a entrada de solutos e destruição da estrutura mitocondrial, e apresentando um
colapso no seu potencial de membrana, translocação da proteína pró- apoptótica Bax para o interior da organela, liberação de cálcio intramitocondrial e consequente aumento do cálcio intracitoplasmático, ativação de caspases efetoras da apoptose e degradação de DNA. Os efeitos fenotípicos e bioquímicos provocados pelo C7A indicam que o composto leve a célula tumoral à morte por um processo apoptótico pela via intrínseca.
• Além da citotoxicidade direta sobre as células tumorais, o ciclopaladado 7A apresentou uma atividade citotóxica direta sobre células endoteliais humanas e inibiu a formação de estruturas pré-angiogênicas in vitro, sugerindo uma adicional atividade anti-angiogênica in vivo.
• A citotoxicidade in vitro de diversos compostos nitrosil tetraamina rutênio foi avaliada em linhagens celulares tumorais murinas e humanas. Esses compostos são doadores de óxido nítrico (NO), e a velocidade com que esse radical é liberado em meio biológico depende do ligante de estabilização acoplado à estrutura do complexo.
• Os resultados com os compostos nitrosil tetraamina rutênio, doadores de óxido nítrico, demonstraram que estes compostos são citotóxicos in vitro para linhagens celulares tumorais murinas e humanas
• Os composto de rutênio trans-[Ru(NO)(NH3)4isn](BF4)3 e trans- [Ru(NO)(NH3)4imN](BF4)3 apresentaram significativa atividade antitumoral in vivo, utilizando o modelo subcutâneo de melanoma murino B16F10-Nex2. Entretanto, a toxicidade destes compostos foi bastante acentuada quando ensaiados in vivo;
• Surpreendentemente, o composto de rutênio trans-
[Ru(NH3)4imN(SO4)]Cl, apresentou uma acentuada atividade antitumoral in vivo, com ausência de efeitos tóxicos nos animais tratados com a
droga;
• A administração intraperitoneal do composto de rutênio trans- [Ru(NH3)4imN(SO4)]Cl, em modelo de metástase também foi capaz de inibir o desenvolvimento de nódulos pulmonares in vivo;
• Aparentemente, a atividade antitumoral do composto sulfatado não se dá apenas pelo sulfato ou ao íon metálico, e sim pela estrutura química como um todo;
• Os resultados para avaliar o mecanismo de ação do composto de rutênio sulfatado sugerem que este quimioterápico provoca apoptose da célula tumoral, já que observamos alterações morfológicas compatíveis com processo apoptótico, bem como externalização de fosfotidilserina e degradação de DNA.
8.0 REFERÊNCIAS BIBLIOGRÁFICAS
Adrain C, Duriez PJ, Brumatti G, Delivani P, Martin SJ The cytotoxic lymphocyte protease, granzyme B, targets the cytoskeleton and perturbs microtubule polymerization dynamics. J Biol Chem. 2006 Mar 24;281(12):8118-25
Alama A, Tasso B, Novelli F, Sparatore F. Organometallic compounds in oncology: implications of novel organotins as antitumor agents. Drug
Discov Today. 2009 May;14(9-10):500-8
Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J. Human ICE/CED-3 protease nomenclature. Cell. 1996 Oct 18;87(2):171
Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR, Harris CC. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Cancer Res. 1998 Jan 15;58(2):334-41.
Andreyev AY, Fahy B, Fiskum G. Cytochrome c release from brain mitochondria is independent of the mitochondrial permeability transition.
FEBS Lett. 1998 Nov 20;439(3):373-6.
Armstrong JS. The role of the mitochondrial permeability transition in cell death. Mitochondrion. 2006 Oct;6(5):225-34.
Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, Neil J, Reis I, Kharfan-Dabaja M, Eckman J, Goodman M, Fernandez HF, Boise LH, Lee KP. 1.Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res. 2002
Dec;8(12):3658-68
Balch CM, Urist MM, Karakousis CP, Smith TJ, Temple WJ, Drzewiecki K, Jewell WR, Bartolucci AA, Mihm MC Jr, Barnhill R, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. 1993 Sep;218(3):262-7
Barbosa CM, Oliveira CR, Nascimento FD, Smith MC, Fausto DM, Soufen MA, Sena E, Araújo RC, Tersariol IL, Bincoletto C, Caires AC. Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells. Eur J Pharmacol. 2006 Aug 7;542(1- 3):37-47
Bertotti M, Mori V, Zanichelli P, Toledo JC, Wagner Franco D. Electrochemical and spectrophotometric methods for evaluation of NO dissociation rate constants from nitrosyl metal complexes activated through reduction.
Methods Enzymol. 2005;396:45-53
Bincoletto C, Tersariol IL, Oliveira CR, Dreher S, Fausto DM, Soufen MA, Nascimento FD, Caires AC. Chiral cyclopalladated complexes derived from
bis(diphenylphosphine)ferrocene ligand as inhibitors of the cathepsin B activity and as antitumoral agents. Bioorg Med Chem. 2005 Apr 15;13(8):3047-55
Boldin MP, Mett IL, Varfolomeev EE, Chumakov I, Shemer-Avni Y, Camonis JH, Wallach D. Self-association of the "death domains" of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J Biol Chem. 1995 Jan 6;270(1):387-91.
Bonati A, Rizzoli V, Lunghi P. Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug. Curr Pharm
Biotechnol. 2006 Dec;7(6):397-405.
Bonavida B, Khineche S, Huerta-Yepez S, Garbán H. Therapeutic potential of nitric oxide in cancer. Drug Resist Updat. 2006 Jun;9(3):157-73
Borges SS, Davanzo CU, Castellano EE, Z-Schpector J, Silva SC, Franco DW. Ruthenium Nitrosyl Complexes with N-Heterocyclic Ligands. Inorg Chem. 1998 Jun 1;37(11):2670-2677.
Brabec V, Kasparkova J. Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist
Updat. 2005 Jun;8(3):131-46.
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248-54
Bras M, Queenan B, Susin SA. Programmed cell death via mitochondria: different modes of dying. Biochemistry. 2005 Feb;70(2):231-9
Browne KA, Johnstone RW, Jans DA, Trapani JA. Filamin (280-kDa actin- binding protein) is a caspase substrate and is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apoptosis. J Biol
Chem. 2000 Dec 15;275(50):39262-6
Caires AC. Recent advances involving palladium (II) complexes for the cancer therapy. Anticancer Agents Med Chem. 2007 Sep;7(5):484-91.
Carvalho AC, Sharpe J, Rosenstock TR, Teles AF, Youle RJ, Smaili SS. Bax affects intracellular Ca2+ stores and induces Ca2+ wave propagation. Cell
Death Differ. 2004 Dec;11(12):1265-76
Casciola-Rosen LA, Miller DK, Anhalt GJ, Rosen A. Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death. J Biol Chem. 1994 Dec 9;269(49):30757-60.
Cepeda V, Fuertes MA, Castilla J, Alonso C, Quevedo C, Pérez JM. Biochemical mechanisms of cisplatin cytotoxicity. Anticancer Agents Med
Chem.2007 Jan;7(1):3-18.
Chudnovsky Y, Khavari PA, Adams AE. Melanoma genetics and the development of rational therapeutics. J Clin Invest. 2005 Apr;115(4):813-24.
Clark DA, Reiner RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origino f familial malignant melanomas from Heritable Melanocytic Lesions. Arch
Dermatol. 1978. 114: 732-738
Clarke MJ. Ruthenium metallopharmaceuticals. Coord. Chem Rev. 2003 236, 209-233
Collery P, Keppler B, Madoulet C, Desoize B. Gallium in cancer treatment.
Crit Rev Oncol Hematol. 2002 Jun; 42(3):283-96.
Cotter TG, Lennon SV, Glynn JM, Green DR. Microfilament-disrupting agents prevent the formation of apoptotic bodies in tumor cells undergoing apoptosis. Cancer Res. 1992 Feb 15;52(4):997-1005
Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol Rev. 2003 Jun;193:10-21.
Croft DR, Coleman ML, Li S, Robertson D, Sullivan T, Stewart CL, Olson MF. Actin-myosin-based contraction is responsible for apoptotic nuclear disintegration. J Cell Biol. 2005 Jan 17;168(2):245-55.
Cullen KJ, Yang Z, Schumaker L, Guo Z. Mitochondria as a critical target of the chemotheraputic agent cisplatin in head and neck cancer. J Bioenerg
Biomembr. 2007 Feb;39(1):43-50).
Danial NN. BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res. 2007 Dec 15;13(24):7254-63
Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J.
Identification of RIP1 kinase as a specific cellular target of necrostatins.
Nat Chem Biol 2008 4: 313-321
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J.2005. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem Biol. 1:112-119
Dias N, Bailly C. Drugs targeting mitochondrial functions to control tumor cell growth. Biochem Pharmacol. 2005 Jul 1;70(1):1-12.
Dilda PJ, Hogg PJ. Arsenical-based cancer drugs. Cancer Treat Rev. 2007 Oct;33(6):542-64
Dua P, Ingle A, Gude RP. Suramin augments the antitumor and antimetastatic activity of pentoxifylline in B16F10 melanoma. Int J Cancer. 2007 Oct 1;121(7):1600-8.
Einhorn LH, Roth BJ, Ansari R, Dreicer R, Gonin R, Loehrer PJ. Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol. 1994 Nov;12(11):2271-6
Ekmekcioglu S, Tang CH, Grimm EA. NO news is not necessarily good news in cancer. Curr Cancer Drug Targets. 2005 Mar;5(2):103-15
Elfering SL, Sarkela TM, Giulivi C. Biochemistry of mitochondrial nitric- oxide synthase. J Biol Chem. 2002 Oct 11;277(41):38079-86
Enari M, Hase A, Nagata S Apoptosis by a cytosolic extract from Fas- activated cells. EMBO J. 1995 Nov 1;14(21):5201-8.
Florea AM, Büsselberg D. Anti-cancer drugs interfere with intracellular calcium signaling. Neurotoxicology. 2009 Sep;30(5):803-10
Freitas ZF, Rodrigues EG, Oliveira V, Carmona AK, Travassos LR. Melanoma heterogeneity: differential, invasive, metastatic properties and profiles of cathepsin B, D and L activities in subclones of the B16F10-NEX2 cell line.
Melanoma Res. 2004 Oct;14(5):333-44
Fuertesa MA, Castillab J, Alonsoa C, Pérez JM. Cisplatin biochemical mechanism of action: from cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways. Curr Med
Chem. 2003 Feb;10(3):257-66
Galanski M, Arion VB, Jakupec MA, Keppler BK. Recent developments in the field of tumor-inhibiting metal complexes. Curr Pharm Des. 2003;9(25):2078-89
Galanski M, Jakupec MA, Keppler BK. Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem. 2005;12(18):2075-94
Gava B, Zorzet S, Spessotto P, Cocchietto M, Sava G. Inhibition of B16 melanoma metastases with the ruthenium complex imidazolium trans- imidazoledimethylsulfoxide-tetrachlororuthenate and down-regulation of tumor cell invasion. J Pharmacol Exp Ther. 2006 Apr;317(1):284-91
Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria as targets for cancer chemotherapy. Semin Cancer Biol. 2009 Feb;19(1):57-66. Epub 2008 Dec 3
Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 2008;18:165–73
Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol. 2000 Mar;2(3):156-62.
Golstein P, Kroemer G. Cell death by necrosis: towards a molecular definition. Trends Biochem Sci. 2007 Jan;32(1):37-43
Gordon DM, Dancis A, Pain D. Mechanisms of mitochondrial protein import.
Essays Biochem. 2000;36:61-73
Gourdier I, Crabbe L, Andreau K, Pau B, Kroemer G. Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA. Oncogene. 2004 Sep 30;23(45):7449-57
Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007 Feb 22;445(7130):851-7.
Green D, Kroemer G. The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol. 1998 Jul;8(7):267-71
Gueders MM, Paulissen G, Crahay C, Quesada-Calvo F, Hacha J, Van Hove C, Tournoy K, Louis R, Foidart JM, Noël A, Cataldo DD. Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding
bronchial responsiveness, inflammation, and cytokine production. Inflamm
Res. 2009 Dec;58(12):845-5
Haak LL, Grimaldi M, Russell JT. Mitochondria in myelinating cells: calcium signaling in oligodendrocyte precursor cells. Cell Calcium. 2000 Nov- Dec;28(5-6):297-306
Hart MM, Adamson RH. Antitumor activity and toxicity of salts of inorganic group 3a metals: aluminum, gallium, indium, and thallium. Proc Natl Acad
Sci U S A. 1971 Jul;68(7):1623-6.
Hebeler-Barbosa F, Rodrigues EG, Puccia R, Caires AC, Travassos LR. Gene Therapy against Murine Melanoma B16F10-Nex2 Using IL-13Ralpha2-Fc Chimera and Interleukin 12 in Association with a Cyclopalladated Drug.
Transl Oncol. 2008 Sep;1(3):110-20
Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M, Elbling L, Micksche M, Keppler B, Berger W. Resistance against novel anticancer metal compounds: differences and similarities. Drug Resist Updat. 2008 Feb-Apr;11(1-2):1-16
Heffeter P, Pongratz M, Steiner E, Chiba P, Jakupec MA, Elbling L, Marian B, Körner W, Sevelda F, Micksche M, Keppler BK, Berger W. Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A). J Pharmacol Exp Ther. 2005 Jan;312(1):281-9.
Henkels KM, Turchi JJ. Cisplatin-induced apoptosis proceeds by caspase- 3-dependent and -independent pathways in cisplatin-resistant and - sensitive human ovarian cancer cell lines. Cancer Res. 1999 Jul 1;59(13):3077-83
Hofheinz RD, Dittrich C, Jakupec MA, Drescher A, Jaehde U, Gneist M, Graf von Keyserlingk N, Keppler BK, Hochhaus A. Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors--a CESAR study (Central European Society for Anticancer Drug Research--EWIV). Int J Clin Pharmacol Ther. 2005 Dec;43(12):590-1
Huerta S, Chilka S, Bonavida B. Nitric oxide donors: novel cancer therapeutics. Int J Oncol. 2008 Nov;33(5):909-27
Ishida S, Lee J, Thiele DJ, Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14298-302
Instituto Nacional do Câncer (INCA). Disponível na internet em http://www.inca.gov.br
Jacobson MD. Programmed cell death: a missing link is found. Trends Cell
Biol. 1997 Dec;7(12):467-9.
Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002 Jan 25;108(2):153-64
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239-57
Khan BT, Bhatt J, Najmuddin K, Shamsuddin S, Annapoorna K. Synthesis, antimicrobial, and antitumor activity of a series of palladium(II) mixed ligand complexes. J Inorg Biochem. 1991 Oct;44(1):55-63
Köpf-Maier P, Köpf H, Neuse EW. Ferricenium complexes: a new type of water-soluble antitumor agent. J Cancer Res Clin Oncol. 1984;108(3):336-40
Köpf-Maier P. Tumor inhibition by ferricenium complexes: systemic effect in vivo and cell growth inhibition in vitro. Z Naturforsch C. 1985 Nov- Dec;40(11-12):843-6.
Kostova I. Ruthenium complexes as anticancer agents. Curr Med Chem. 2006;13(9):1085-107.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G; Nomenclature Committee on Cell Death 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009 Jan;16(1):3-11
Kroemer, G and Martin, S.J. 2005. Caspase-independent cell death. Nat Med. 11: 725-730
Ku NO, Liao J, Omary MB. Apoptosis generates stable fragments of human type I keratins. J Biol Chem. 1997 Dec 26;272(52):33197-203
La Porta CA. Drug resistance in melanoma: new perspectives. Curr Med
Chem. 2007;14(4):387-91
Larochette N, Decaudin D, Jacotot E, Brenner C, Marzo I, Susin SA, Zamzami N, Xie Z, Reed J, Kroemer G. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res. 1999 Jun 15;249(2):413-21
Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008 Oct 20;27(48):6194-206.
Louie AY, Meade TJ. Metal complexes as enzyme inhibitors. Chem Rev. 1999 Sep 8;99(9):2711-34
Maksimovic-Ivanic D, Mijatovic S, Harhaji L, Miljkovic D, Dabideen D, Fan Cheng K, Mangano K, Malaponte G, Al-Abed Y, Libra M, Garotta G, Nicoletti F, Stosic-Grujicic S. Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo. Mol Cancer Ther. 2008 Mar;7(3):510-20
Martin SJ, Finucane DM, Amarante-Mendes GP, O'Brien GA, Green DR. Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem. 1996 Nov 15;271(46):28753-6
Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp
Med. 1995 Nov 1;182(5):1545-56
Matesanz AI, Souza P. Palladium and platinum 3,5-diacetyl-1,2,4-triazol bis(thiosemicarbazones): chemistry, cytotoxic activity and structure- activity relationships. J Inorg Biochem. 2007 Feb;101(2):245-53
McKeage MJ. Gold opens mitochondrial pathways to apoptosis. Br J
Pharmacol. 2002 Aug;136(8):1081-2.
Mocellin S, Bronte V, Nitti D. Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Med Res Rev. 2007 May;27(3):317-52.
Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma.
Oncologist. 2001;6 Suppl 2:17-21
Navarro-Ranninger C, Pérez JM, Zamora F, González VM, Masaguer JR, Alonso C. Palladium (II) compounds of putrescine and spermine. Synthesis, characterization, and DNA-binding and antitumor properties. J
Nutt LK, Pataer A, Pahler J, Fang B, Roth J, McConkey DJ, Swisher SG. Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores. J Biol Chem. 2002 Mar 15;277(11):9219-25
Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer. 2004 Aug;4(8):592-603
Oliveira CR, Barbosa CM, Nascimento FD, Lanetzki CS, Meneghin MB, Pereira FE, Paredes-Gamero EJ, Ferreira AT, Rodrigues T, Queiroz ML, Caires AC, Tersariol IL, Bincoletto C. Pre-clinical antitumour evaluation of Biphosphinic Palladacycle Complex in human leukaemia cells. Chem Biol Interact. 2009 Feb 12;177(3):181-9
Oliveira Fde S, Ferreira KQ, Bonaventura D, Bendhack LM, Tedesco AC, Machado Sde P, Tfouni E, da Silva RS. The macrocyclic effect and vasodilation response based on the photoinduced nitric oxide release from trans-[RuCl(tetraazamacrocycle)NO](2+). J Inorg Biochem. 2007 Feb;101(2):313-20
Ott I, Gust R. Non platinum metal complexes as anti-cancer drugs. Arch
Pharm (Weinheim). 2007 Mar;340(3):117-26
Pacher P, Thomas AP, Hajnóczky G. Ca2+ marks: miniature calcium signals in single mitochondria driven by ryanodine receptors. Proc Natl Acad Sci U
Pan RS, Dilley RA. Influence of Ca(2+) on the thylakoid lumen violaxanthin de-epoxidase activity through Ca(2+) gating of H(+) flux at the CF(o) H(+) channel. Photosynth Res. 2000;65(2):141-54
Paschoalin T, Carmona AK, Rodrigues EG, Oliveira V, Monteiro HP, Juliano MA, Juliano L, Travassos LR. Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth. Mol Cancer. 2007 Jul 9;6:44
Piccioli F, Sabatini S, Messori L, Orioli P, Hartinger ChG, Keppler BK. A comparative study of adduct formation between the anticancer ruthenium(III) compound HInd trans-[RuCl4(Ind)2] and serum proteins. J
Inorg Biochem. 2004 Jun;98(6):1135-42
Pillarsetty N, Katti KK, Hoffman TJ, Volkert WA, Katti KV, Kamei H, Koide T. In vitro and in vivo antitumor properties of tetrakis((trishydroxy- methyl)phosphine)gold(I) chloride. J Med Chem. 2003 Mar 27;46(7):1130-2
Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Rizzuto R. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J. 2001 Jun 1;20(11):2690-701
Pluim D, van Waardenburg RC, Beijnen JH, Schellens JH. Cytotoxicity of the organic ruthenium anticancer drug Nami-A is correlated with DNA binding in four different human tumor cell lines. Cancer Chemother Pharmacol. 2004 Jul;54(1):71-8
Portugal J, Bataller M, Mansilla S. Cell death pathways in response to antitumor therapy. Tumori. 2009 Jul-Aug;95(4):409-21
Pratt MR, Sekedat MD, Chiang KP, Muir TW. Direct measurement of cathepsin B activity in the cytosol of apoptotic cells by an activity-based probe. Chem Biol. 2009 Sep 25;16(9):1001-12
Rademaker-Lakhai JM, van den Bongard D, Pluim D, Beijnen JH, Schellens JH A Phase I and pharmacological study with imidazolium-trans-DMSO- imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent.. Clin
Cancer Res. 2004 Jun 1;10(11):3717-27
Rao L, Perez D, White E. Lamin proteolysis facilitates nuclear events during apoptosis. J Cell Biol. 1996 Dec;135(6 Pt 1):1441-55
Rasey JS, Nelson NJ, Larson SM Tumor cell toxicity of stable gallium nitrate: enhancement by transferrin and protection by iron. Eur J Cancer
Clin Oncol. 1982 Jul;18(7):661-8
Reed JC. Apoptosis-regulating proteins as targets for drug discovery.
Trends Mol Med. 2001 Jul;7(7):314-9
Robb-Gaspers LD, Burnett P, Rutter GA, Denton RM, Rizzuto R, Thomas AP. Integrating cytosolic calcium signals into mitochondrial metabolic responses. EMBO J. 1998 Sep 1;17(17):4987-5000
Rodrigues EG, Silva LS, Fausto DM, Hayashi MS, Dreher S, Santos EL, Pesquero JB, Travassos LR, Caires AC. Cyclopalladated compounds as
chemotherapeutic agents: antitumor activity against a murine melanoma cell line. Int J Cancer. 2003 Nov 10;107(3):498-504
Rosenberg B, VanCamp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumour agents. Nature. 1969 Apr 26;222(5191):385- 6
Rosenblatt J, Raff MC, Cramer LP. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol. 2001 Nov 27;11(23):1847-57
Saikumar P, Dong Z, Mikhailov V, Denton M, Weinberg JM, Venkatachalam MA. Apoptosis: definition, mechanisms, and relevance to disease. Am J
Med. 1999 Nov;107(5):489-506
Santana DP, Faria PA, Paredes-Gamero EJ, Caires AC, Nantes IL, Rodrigues T. Palladacycles catalyse the oxidation of critical thiols of the mitochondrial membrane proteins and lead to mitochondrial permeabilization and cytochrome c release associated with apoptosis.
Biochem J. 2009 Jan 1;417(1):247-56
Schulze-Osthoff K, Walczak H, Dröge W, Krammer PH. Cell nucleus and DNA