title: A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells.
abstract: BACKGROUND
  Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd(2) [S((-))C(2), N-dmpa](2) (μ-dppe)Cl(2)} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.
  
  
  METHODS
  B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a.
  
  
  RESULTS
  Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.
  
  
  CONCLUSIONS
  The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.
authors.affiliation: Unidade de Oncologia Experimental, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Fabiana A
authors.initials: FA
authors.lastname: Serrano
authors.forename: Alisson L
authors.initials: AL
authors.lastname: Matsuo
authors.forename: Priscila T
authors.initials: PT
authors.lastname: Monteforte
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bechara
authors.forename: Soraya S
authors.initials: SS
authors.lastname: Smaili
authors.forename: Débora P
authors.initials: DP
authors.lastname: Santana
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Felipe V
authors.initials: FV
authors.lastname: Pereira
authors.forename: Luis S
authors.initials: LS
authors.lastname: Silva
authors.forename: Joel
authors.initials: J
authors.lastname: Machado
authors.forename: Edson L
authors.initials: EL
authors.lastname: Santos
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Martins
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
authors.forename: Antonio C F
authors.initials: AC
authors.lastname: Caires
authors.forename: Elaine G
authors.initials: EG
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; D051028:bcl-2-Associated X Protein; D010165:Palladium; D020169:Caspases; D002945:Cisplatin