Inhibition of P-Selectin and PSGL-1 Using Humanized Monoclonal Antibodies Increases the Sensitivity of Multiple Myeloma Cells to Bortezomib.

Barbara Muz,Feda Azab,Abdel Kareem Azab,Pilar De La Puente,Ziad Kawar,Scott Rollins,Richard Alvarez

doi:10.1155/2015/417586

Barbara Muz, Feda Azab + Show 5 more

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https://doi.org/10.1155/2015/417586

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Abstract

Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow. Despite the introduction of novel therapies majority of MM patients relapse. We have previously shown that inhibition of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) play a key role in proliferation of MM and using small-molecule inhibitors of P-selectin/PSGL-1 sensitized MM cells to therapy. However, these small-molecule inhibitors had low specificity to P-selectin and showed poor pharmacokinetics. Therefore, we tested blocking of P-selectin and PSGL-1 using functional monoclonal antibodies in order to sensitize MM cells to therapy. We have demonstrated that inhibiting the interaction between MM cells and endothelial and stromal cells decreased proliferation in MM cells and in parallel induced loose-adhesion to the primary tumor site to facilitate egress. At the same time, blocking this interaction in vivo led to MM cells retention in the circulation and delayed homing to the bone marrow, thus exposing MM cells to bortezomib which contributed to reduced tumor growth and better mice survival. This study provides a better understanding of the biology of P-selectin and PSGL-1 and their roles in dissemination and resensitization of MM to treatment.

Highlights

Multiple myeloma (MM) is a plasma cell malignancy located mainly in the bone marrow (BM), characterized by continuous dissemination of cancer cells [1, 2]
We found that after blocking P-selectin using a single concentration of SelG1 (10 μg/mL) on stromal cells H929 adhesion was decreased by 60% and MM1.s by 20% (Figure 1(c)); or on endothelial cells H929 adhesion was decreased by 43% and MM1.s by 23% (Figure 1(d))
After blocking PSGL-1 on MM cells using a single concentration of SelK2 (10 μg/mL), H929 cell adhesion was decreased by 50% and MM1.s by 12% in coculture with stromal cells (Figure 1(e)), or H929 cell adhesion was decreased by 28% and MM1.s by 40% in coculture with endothelial cells (Figure 1(f))

Summary

Introduction

Multiple myeloma (MM) is a plasma cell malignancy located mainly in the bone marrow (BM), characterized by continuous dissemination of cancer cells [1, 2]. Selectins (CD62) are cell surface lectin-like adhesion molecules which bind sugar polymers and are involved in lymphocyte extravasation, especially during inflammation and cancer metastasis [8]. P-selectin travels to the cell surface and can bind to ligands expressed on both leukocytes and cancer cells. The selectins and ligands interact rapidly in order to facilitate tethering, followed by rapid dissociation to enable rolling on the endothelium and cell extravasation [9]. P-selectin glycoprotein ligand-1 (PSGL-1, CD162) is the best characterized ligand for all three types of selectins and is expressed on myeloid, lymphoid, and dendritic cells [10]. PSGL-1 has especially high affinity for P-selectin on intact leukocytes compared to other ligands and is essential for adhesion to P-selectin [12, 13]

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