Cocultures of metastatic and host immune cells: selective effects of NAMI-A for tumor cells.
The effects of NAMI-A, [H2im][trans-RuCl4(dmso-S)(Him)], a new metal-based agent for treating tumor metastases, have been investigated in vitro on splenocytes, ConA- or LPS-activated T and B lymphoblasts, and thymocytes. Splenocytes and thymocytes exposed for 1 h to 0.01-0.1-mM NAMI-A do not change their mitochondrial functionality, cell cycle distribution, protein synthesis, and CD44 expression in comparison to untreated control samples. Instead, mitochondrial functionality increased 24 h after treatment in a fraction of splenocytes. The same treatment reduced mitochondrial functionality and S phase of the cell cycle in T and B blasts (already after 1 h treatment) and reduced CD44 expression on B blasts, 24 h after treatment. On cocultures of splenocytes and metastatic cells (metGM) (1:1), NAMI-A induces a selective depolarization of mitochondrial membrane potential of metGM cells, while it stimulates splenocytes (mainly lymphocytes), as shown by the increase of the S phase, nitric oxide production, and adhesion onto metastatic cells. This, in turn, reduces the number of metastatic cells and results in the increased ratio between splenocytes and metGM in favor of diploid cells (doubling from one to two). Rosetting of leukocytes onto metastatic cells correlates with induction of CD54 expression on tumor cells after NAMI-A in vivo treatment, which in turn, might contribute to metastasis recognition by cytotoxic lymphocytes. The overall antimetastatic activity displayed by NAMI-A might therefore be the result of complex interactions with tumor cells, on which it displays selective antitumor activity, and with host immune cells through which it promotes activation of host immune defenses involved in tumor suppression.
Bacac
Marina
M
Department of Biomedical Sciences, University of Trieste, Via L. Giorgieri 7, 34127 Trieste, Italy.
Vadori
Marta
M
Sava
Gianni
G
Pacor
Sabrina
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018920:Coculture Techniques; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018960:Hyaluronan Receptors / Q000032:analysis; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008855:Microscopy, Electron, Scanning; D009362:Neoplasm Metastasis / Q000276:immunology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000096:biosynthesis; D009942:Organometallic Compounds / Q000494:pharmacology*; D017975:Ruthenium Compounds
D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D009569:Nitric Oxide; D004121:Dimethyl Sulfoxide