Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.
All types of amyloidosis are structurally characterized by the cross beta-pleated sheet conformation of the fibrils, irrespective of their biochemical composition. The clinical observation that the anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDOX) can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis was the starting point for this investigation of its possible mechanism of action. IDOX binds strongly to all five types of natural amyloid fibrils tested: immunoglobulin light chains, amyloid A, transthyretin (methionine-30 variant), beta-protein (Alzheimer), and beta 2-microglobulin. Quantitative binding studies showed that IDOX, but not doxorubicin, binds strongly to amyloid fibrils. This binding is saturable and involves two apparently distinct binding sites with Kd values of 5.9 x 10(-11) M and 3.4 x 10(-9) M. IDOX inhibited in vitro insulin amyloid fibrillogenesis. In vivo studies using the experimental amyloid murine model confirmed the specific targeting of IDOX to amyloid deposits. Preincubation of amyloid enhancing factor with IDOX significantly reduced the formation of amyloid deposits. It is hypothesized that IDOX exerts its beneficial effects through the inhibition of fibril growth, thus increasing the solubility of existing amyloid deposits and facilitating their clearance. IDOX may represent the progenitor of a class of amyloid-binding agents that could have both diagnostic and therapeutic potential in all types of amyloidoses.
Merlini
G
G
Institute of Clinical Medicine II, University Hospital S. Matteo, Pavia, Italy.
Ascari
E
E
Amboldi
N
N
Bellotti
V
V
Arbustini
E
E
Perfetti
V
V
Ferrari
M
M
Zorzoli
I
I
Marinone
M G
MG
Garini
P
P
D000682:Amyloid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000686:Amyloidosis / Q000517:prevention & control*; D000818:Animals; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006023:Glycoproteins; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011228:Prealbumin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017433:Protein Structure, Secondary; D000685:Serum Amyloid A Protein / Q000032:analysis; D013154:Spleen / Q000187:drug effects / Q000473:pathology
D000682:Amyloid; D006023:Glycoproteins; D007147:Immunoglobulin Light Chains; D007328:Insulin; D011228:Prealbumin; D000685:Serum Amyloid A Protein; C046748:amyloid enhancing factor; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin