Prevention of mantle lymphoma tumor establishment by routing transferrin receptor toward lysosomal compartments.
Mantle cell lymphoma (MCL) is one of the most frequent of the newly recognized non-Hodgkin's lymphomas. The major problem of MCL therapy is the occurrence of relapse and subsequent resistance to chemotherapy and immunotherapy in virtually all cases. Here, we show that one injection of anti-human transferrin receptor (TfR) monoclonal antibody A24 totally prevented xenografted MCL tumor establishment in nude mice. It also delayed and inhibited tumor progression of established tumors, prolonging mice survival. In vitro, A24 induced up to 85% reduction of MCL cell proliferation (IC(50) = 3.75 nmol/L) independently of antibody aggregation, complement-dependent or antibody-dependent cell-mediated cytotoxicity. A24 induced MCL cell apoptosis through caspase-3 and caspase-9 activation, either alone or synergistically with chemotherapeutic agents. A24 induced TfR endocytosis via the clathrin adaptor protein-2 complex pathway followed by transport to lysosomal compartments. Therefore, A24-based therapies alone or in association with classic chemotherapies could provide a new alternative strategy against MCL, particularly in relapsing cases.
Lepelletier
Yves
Y
Centre National de la Recherche Scientifique UMR 8147, Université Paris V, Hôpital Necker, 161 rue de Sevres, 75015 Paris, France.
Camara-Clayette
Valérie
V
Jin
Hulin
H
Hermant
Aurélie
A
Coulon
Séverine
S
Dussiot
Michaël
M
Arcos-Fajardo
Michelle
M
Baude
Cédric
C
Canionni
Danielle
D
Delarue
Richard
R
Brousse
Nicole
N
Benaroch
Philippe
P
Benhamou
Marc
M
Ribrag
Vincent
V
Monteiro
Renato C
RC
Moura
Ivan C
IC
Hermine
Olivier
O
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011990:Receptors, Transferrin / Q000276:immunology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D011990:Receptors, Transferrin