Reduction of in vivo lung metastases by dinuclear ruthenium complexes is coupled to inhibition of in vitro tumour invasion.
Mononuclear ruthenium-dmso compounds showed interesting antimetastatic properties on experimental models of solid tumours. In line with the interesting results with multinuclear platinum complexes, which proved to overcome cisplatin resistance, we thought it worthwhile to test the pharmacological properties of some dinuclear ruthenium complexes to ascertain the possible advantages due to the introduction of a second metal centre over NAMI-A and its mononuclear analogues. These compounds belong to the general formula X2[[RuCl4(dmso-S)]2(mu-L)] or [X][[RuCl4(dmso-S)](mu-L)[RuCl3(dmso-S)(dmso-O)]] where L is a nitrogen donor ligand (pyrazine; pyrimidine; 4,4'-bipyridine; 1,2-bis(4-pyridyl)ethane; 1,2-bis(4-pyridyl) ethylene; 1,3-bis(4-pyridyl)propane) and X a counterion. We focused on parameters related to metastatic ability such as gelatinase activity, detected by zymography, and invasive potential, measured by means of a transwell chamber. These activities were correlated to the ability to inhibit tumour metastases in vivo. All dinuclear complexes, except compound D8 ([NH4]2[[RuCl4(dmso-S)]2(mu-pyz]), decrease the number of tumour cells that cross a matrigel barrier, and inhibit MMP-9 gelatinolytic activity at concentrations lower than that of NAMI-A and of other mononuclear ruthenium complexes. In vivo compounds D5 (Na2[[RuCl4(dmso-S)]2(mu-ethylbipy)]) and D7 ([NH4][[RuCl4(dmso-S)](mu-pyz)[RuCl3(dmso-S) (dmso-O)]]) show anti-metastasis activity, at two dose levels, with mild or null effect on primary tumour growth; compound D8 is the weakest active. All compounds tend to accumulate in liver and kidneys, rather than in tumour and lungs. However, compound D5, the most active in vitro on invasion and gelatinases and active in vivo on metastasis, is better concentrated in the lungs than compound D8 which is less active or inactive in vitro and in vivo. Histological analysis show liver, as well as kidney toxicities that limit in vivo activity. These data thus suggest dinuclear ruthenium complexes as promising anti-invasive agents for cancer treatment.
Bergamo
Alberta
A
Foundation Callerio-Onlus, I-34127 Trieste, Italy. a.bergamo@callerio.org
Stocco
Gabriele
G
Casarsa
Claudia
C
Cocchietto
Moreno
M
Alessio
Enzo
E
Serli
Barbara
B
Zorzet
Sonia
S
Sava
Gianni
G
D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008956:Models, Chemical; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D012428:Ruthenium / Q000494:pharmacology*; D017975:Ruthenium Compounds; D014018:Tissue Distribution
D004338:Drug Combinations; D007797:Laminin; D008024:Ligands; D009942:Organometallic Compounds; D011509:Proteoglycans; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); C059485:matrigel; D012428:Ruthenium; D003094:Collagen; D020780:Matrix Metalloproteinase 9; D004121:Dimethyl Sulfoxide