The role of cisplatin and NAMI-A plasma-protein interactions in relation to combination therapy.
The aim of the study is to evaluate the differences of protein binding of NAMI-A, a new ruthenium drug endowed with selective antimetastatic properties, and of cisplatin and to ascertain the possibility to use two drugs based on heavy metals in combination to treat solid tumour metastases. For this purpose, we have developed a technique that allows the proteins, to which metal drugs bind, to be identified from real protein mixtures. Following incubation with the drugs, the bands containing platinum and/or ruthenium are separated by native PAGE, SDS-PAGE and 2D gel electrophoresis, and identified using laser ablation inductively coupled plasma mass spectrometry. Both drugs interact with essentially the same proteins which, characterised by proteomics, are human serum albumin precursor, macroglobulin alpha2 and human serotransferrin precursor. The interactions of NAMI-A are largely reversible whereas cisplatin forms stronger interactions that are less reversible. These data correlate well with the MCa mammary carcinoma model on which full doses of NAMI-A combined with cisplatin show additive effects as compared to each treatment taken alone, independently of whether NAMI-A precedes or follows cisplatin. Furthermore, the implication from this study is that the significantly lower toxicity of NAMI-A, compared to cisplatin, could be a consequence of differences in the mode of binding to plasma proteins, involving weaker interactions compared to cisplatin.
Khalaila
Isam
I
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, EPFL, CH-1015 Lausanne, Switzerland.
Bergamo
Alberta
A
Bussy
Francois
F
Sava
Gianni
G
Dyson
Paul J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism* / Q000627:therapeutic use; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000378:metabolism* / Q000627:therapeutic use; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism*; D017975:Ruthenium Compounds; D012709:Serum Albumin / Q000378:metabolism*; D013997:Time Factors; D014168:Transferrin / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism*
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011498:Protein Precursors; D017975:Ruthenium Compounds; D012709:Serum Albumin; D014168:Transferrin; D000511:alpha-Macroglobulins; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D002945:Cisplatin; D004121:Dimethyl Sulfoxide