Bortezomib Overcomes Cell Adhesion-Mediated Drug Resistance Via Down-Regulation of VLA-4 Expression in Multiple Myeloma

• Published in: Blood Vol. 112; no. 11; p. 1634
• Main Authors: Hatano, Kaoru, Kikuchi, Jiro, Takatoku, Masaaki, Shimizu, Rumi, Wada, Taeko, Ueda, Masuzu, Nobuyoshi, Masaharu, Oh, Iekuni, Sato, Kazuya, Suzuki, Takahiro, Ozaki, Katsutoshi, Mori, Masaki, Nagai, Tadashi, Muroi, Kazuo, Kano, Yasuhiko, Furukawa, Yusuke, Ozawa, Keiya
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.11.2008
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.1634.1634

Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using shRNA to define the molecule(s) responsible for CAM-DR of MM. Using 4 bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226, and U266) and primary myeloma cells, we identified CD29 (b1-integrin), CD44, CD49d (a4-integrin, a subunit of VLA-4), CD54 (ICAM-1), CD138 (syndecan-1) and CD184 (CXCR4) as major adhesion molecules expressed on MM. Short hairpin RNA-mediated knockdown of CD49d but not CD44, CD54, CD138, and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin, and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically down-regulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.