Abstract
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a short median survival despite multimodal therapy. FTY720, an immunosuppressive drug approved for the treatment of multiple sclerosis, promotes MCL cell death concurrent with down-modulation of phospho-Akt and cyclin D1 and subsequent cell-cycle arrest. However, the mechanism of FTY720-mediated MCL cell death remains to be fully clarified. In the present study, we show features of autophagy blockage by FTY720 treatment, including accumulation of autolysosomes and increased LC3-II and p62 levels. We also show that FTY720-induced cell death is mediated by lysosomal membrane permeabilization with subsequent translocation of lysosomal hydrolases to the cytosol. FTY720-mediated disruption of the autophagic-lysosomal pathway led to increased levels of CD74, a potential therapeutic target in MCL that is degraded in the lysosomal compartment. This finding provided rationale for examining combination therapy with FTY720 and milatuzumab, an anti-CD74 mAb. Treatment of MCL cell lines and primary tumor cells with FTY720 and milatuzumab resulted in statistically significant enhanced cell death, which was synergistic in blastic variant MCL cell lines. Significant in vivo therapeutic activity of combination treatment was also demonstrated in a preclinical, in vivo model of MCL. These findings support clinical evaluation of this combination in patients with MCL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / administration & dosage
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / metabolism*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Autophagy / drug effects
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Cell Death / drug effects
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Cell Line, Tumor
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Drug Synergism
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Female
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Fingolimod Hydrochloride
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Gene Expression Regulation, Neoplastic / drug effects
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism*
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Humans
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Immunoblotting
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Immunosuppressive Agents / pharmacology
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Lymphoma, Mantle-Cell / drug therapy*
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Lymphoma, Mantle-Cell / metabolism
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Lymphoma, Mantle-Cell / pathology
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Lysosomes / metabolism
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Mice
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Mice, SCID
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Microscopy, Confocal
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Microtubule-Associated Proteins / metabolism
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Propylene Glycols / administration & dosage
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Propylene Glycols / pharmacology*
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Protein Transport / drug effects
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Reverse Transcriptase Polymerase Chain Reaction
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Sphingosine / administration & dosage
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal, Humanized
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Antigens, Differentiation, B-Lymphocyte
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Histocompatibility Antigens Class II
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Immunosuppressive Agents
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MAP1LC3A protein, human
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Microtubule-Associated Proteins
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Propylene Glycols
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invariant chain
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milatuzumab
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Fingolimod Hydrochloride
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Sphingosine