Muz Barbara, Azab Feda, de la Puente Pilar, Rollins Scott, Alvarez Richard, Kawar Ziad, Azab Abdel Kareem
Cancer Biology Division, Department of Radiation Oncology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63108, USA.
Selexys Pharmaceuticals, 840 Research Parkway, Suite 510, Oklahoma City, OK 73104, USA.
Biomed Res Int. 2015;2015:417586. doi: 10.1155/2015/417586. Epub 2015 Oct 11.
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.
多发性骨髓瘤（MM）是一种局限于骨髓的浆细胞恶性肿瘤。尽管引入了新型疗法，但大多数MM患者仍会复发。我们之前已经表明，抑制P-选择素和P-选择素糖蛋白配体-1（PSGL-1）在MM增殖中起关键作用，并且使用P-选择素/PSGL-1的小分子抑制剂可使MM细胞对治疗敏感。然而，这些小分子抑制剂对P-选择素的特异性较低，并且药代动力学较差。因此，我们测试了使用功能性单克隆抗体阻断P-选择素和PSGL-1，以使MM细胞对治疗敏感。我们已经证明，抑制MM细胞与内皮细胞和基质细胞之间的相互作用会降低MM细胞的增殖，并同时诱导其与原发性肿瘤部位的松散粘附，以促进其逸出。同时，在体内阻断这种相互作用会导致MM细胞滞留在循环中，并延迟归巢至骨髓，从而使MM细胞暴露于硼替佐米，这有助于减少肿瘤生长并提高小鼠存活率。这项研究有助于更好地理解P-选择素和PSGL-1的生物学特性及其在MM的播散和重新致敏治疗中的作用。
