Copanlisib, a novel phosphoinositide 3-kinase inhibitor, combined with carfilzomib inhibits multiple myeloma cell proliferation
Multiple myeloma (MM) is a uniformly fatal disorder of B cells characterized by the accumulation of abnormal plasma cells. Phosphoinositide 3-kinase (PI3K) signaling pathways play a critical regulatory role in MM pathology. Copanlisib, also known as BAY80-6946, is a potent PI3Kα and δ inhibitor. In this study, we investigated the efficacy of copanlisib and a proteasome inhibitor using MM cell lines and primary samples. The p110α and δ catalytic subunits of the class PI3K increased, and carfilzomib activity reduced in the presence of a supernatant from the feeder cell line, HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) partially reduced upon carfilzomib treatment in the presence of HS-5. Apoptosis also decreased. Copanlisib treatment for 72 h inhibited growth in MM cell lines and induced apoptosis. Combination treatment of MM cells with carfilzomib and copanlisib caused greater cytotoxicity than that caused by either drug alone and increased apoptosis. Caspase 3 activity increased while that of Akt decreased after combination treatment with copanlisib and carfilzomib. Further, copanlisib inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in vitro and in vivo. It also inhibited C-X-C motif chemokine 12 (CXCL12)-mediated chemotaxis. The data suggest that administration of the PI3K inhibitor, copanlisib, may be a powerful strategy against stroma-associated drug resistance of MM cells and can enhance the cytotoxic effects of proteasome inhibitors in such residual MM cells.
KeywordsMultiple myeloma PI3K p110δ Proteasome inhibitor Feeder cell
We thank the Tokyo Medical University Research Center for providing technical support.
Conception and design: S Okabe, Y Tanaka, T Tauchi, and K Ohyashiki. Development of methodology: S Okabe, Y Tanaka, T Tauchi, and K Ohyashiki. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S Okabe, Y Tanaka, and T Tauchi. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S Okabe, Y Tanaka, and T Tauchi. Writing, review, and/or revision of the manuscript: S Okabe, Y Tanaka, T Tauchi, and K Ohyashiki. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S Okabe, Y Tanaka, T Tauchi, and K Ohyashiki.
This work was supported by a High-Tech Research Center Project for private universities, a matching fund subsidy from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), and by the University-Industry Joint Research Project for private universities (another matching fund subsidy from MEXT). This work was also supported by grants-in-aid for Scientific Research from MEXT and Supporting Positive Activities for Female Researchers. In addition, the study was supported by a grant from the Bristol-Myers Squibb Company.
Compliance with ethical standards
This study protocol was approved by the Institutional Review Board of the Tokyo Medical University (No. 1974, H-28026).
Conflict of interest
The authors declare that they have no conflicts of interest.
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