Inhibition of NF-kappaB and Akt pathways by an antibody-avidin fusion protein sensitizes malignant B-cells to cisplatin-induced apoptosis.
Multiple myeloma (MM) is an incurable disease of malignant plasma cells. Recent therapeutic advancements have resulted in improved response rates, however, there is no improvement in overall survival, therefore, new therapeutics are needed. Since the transferrin receptor is upregulated on the surface of MM cells, we previously developed an antibody fusion protein consisting of an IgG3 specific for the human transferrin receptor 1 (TfR1, CD71) genetically fused to avidin at its carboxy-terminus (ch128.1Av). We have previously shown that ch128.1Av exhibits intrinsic cytotoxicity against certain malignant B-cells by disrupting the cycling of the TfR and decreasing TfR cell surface expression resulting in lethal iron starvation. In addition, ch128.1Av can sensitize malignant cells to apoptosis induced by gambogic acid, a herbal drug used in Chinese medicine. In this study, we hypothesized that ch128.1Av may also sensitize drug-resistant malignant B-cells to chemotherapeutic agents by inhibiting key survival pathways. In this study we show that ch128.1Av sensitizes malignant B-cells to apoptosis induced by cisplatin (CDDP). The sensitization by ch128.1Av resulted in the inhibition of the constitutively activated Akt and NF-kappaB survival/antiapoptotic pathways and downstream decreased expression of antiapoptotic gene products such as BclxL and survivin. The direct role of the inhibition of the Akt and NF-kappaB pathways by ch128.1Av in CDDP-mediated cytotoxicity was demonstrated by the use of specific chemical inhibitors and siRNA which mimicked the effects of ch128.1Av. Overall, this study provides evidence of the therapeutic potential of ch128.1Av as a chemo-sensitizing agent in drug-resistant tumor cells.
Suzuki
Eriko
E
Department of Urology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 165-8582, Japan.
Daniels
Tracy R
TR
Helguera
Gustavo
G
Penichet
Manuel L
ML
Umezawa
Kazuo
K
Bonavida
Benjamin
B
D000906:Antibodies / Q000737:chemistry*; D017209:Apoptosis; D001360:Avidin / Q000737:chemistry*; D001402:B-Lymphocytes / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008516:Medicine, Chinese Traditional; D053078:Membrane Potential, Mitochondrial; D009101:Multiple Myeloma / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry*; D044004:Xanthones / Q000737:chemistry
D000906:Antibodies; D007074:Immunoglobulin G; D016328:NF-kappa B; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D044004:Xanthones; D001360:Avidin; C052659:gambogic acid; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin