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Copanlisib, a novel phosphoinositide 3-kinase inhibitor, combined with carfilzomib inhibits multiple myeloma cell proliferation

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Abstract

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.

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Acknowledgments

We thank the Tokyo Medical University Research Center for providing technical support.

Funding

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.

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Author notes

  1. Seiichi Okabe and Yuko Tanaka contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan

    Seiichi Okabe, Yuko Tanaka, Tetsuzo Tauchi & Kazuma Ohyashiki

Authors
  1. Seiichi Okabe
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  2. Yuko Tanaka
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  3. Tetsuzo Tauchi
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  4. Kazuma Ohyashiki
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Contributions

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.

Corresponding author

Correspondence to Seiichi Okabe.

Ethics declarations

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.

Electronic supplementary material

Supplemental Fig. 1

Carfilzomib efficacy was decreased by the HS-5 supernatant. (a) U266 and RPMI8226 cells were co-cultured with or without HS-5 and treated with the indicated concentration of carfilzomib for 72 h. Percentage cell growth was determined. *P < 0.05 compared to control. Results represent three separate experiments. (PNG 220 kb)

High resolution image (TIF 28 kb)

Supplemental Fig. 2

Efficacy of copanlisib and carfilzomib in myeloma cells. (a, b) U266 or RPMI8226 cells were treated with the indicated concentrations of carfilzomib or bortezomib and/or copanlisib for 72 h. The relative cytotoxic rates were determined. (PNG 1120 kb)

High resolution image (TIF 155 kb)

Supplemental Fig. 3

Efficacy of PI3K isoform-specific inhibitors and carfilzomib in myeloma cells. (a) RPMI8226 cells were treated with carfilzomib and/or pictilisib, alpelisib, idelalisib, and carfilzomib with alpelisib plus idelalisib for 72 h, after which relative cell growth rates were determined. The data shown represent three independent experiments. *P < 0.05, compared with alpelisib or idelalisib treatment. (PNG 186 kb)

High resolution image (TIF 76 kb)

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Okabe, S., Tanaka, Y., Tauchi, T. et al. Copanlisib, a novel phosphoinositide 3-kinase inhibitor, combined with carfilzomib inhibits multiple myeloma cell proliferation. Ann Hematol 98, 723–733 (2019). https://doi.org/10.1007/s00277-018-3547-7

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  • DOI: https://doi.org/10.1007/s00277-018-3547-7

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