Abstract
Revlimid® (Lenalidomide, CC-5013) and CC-4047 are IMiDs® immunomodulatory drugs that have been described as having immunomodulatory properties and anti-tumor activity. Here we report proapoptotic effects of CC-5013 and CC-4047 on tumor cells in a co-culture model of PBMC and tumor cells. CC-5013 and CC-4047 enhanced PBMC activity leading to tumor cell apoptosis in K562/PBMC co-culture model. We also demonstrate that the natural killer (NK) cell population of PBMC was essential in inducing K562 apoptosis. Increases of NK and natural killer T (NKT) cell populations by CC-5013 and CC-4047 was observed along with modulation of NK cell CD56 adhesion marker. In addition, our data indicate that NK activation by CC-4047 was dependent on other cell types of PBMC. We expanded the application of K562/PBMC co-culture model to other hematological and solid tumors. In Raji/PBMC co-culture model, CC-5013 and CC-4047 dose-dependently augmented tumor cell apoptosis. Pre-treatment of Raji cells with Rituximab further enhanced apoptosis induced by CC-5013 or CC-4047-treated PBMC. Moreover, CC-5013 and CC-4047 significantly increased PC-3 prostate cancer cell apoptosis in PC-3/PBMC co-culture, either as single agent or in combination with Docetaxel. Together, the results reveal that co-culture models are suitable cellular systems to assess anti-tumor activities of these compounds. Our findings support clinical evaluation of CC-5013 and CC-4047 in relapsed NHL with Rituximab and in prostate cancer with Docetaxel.
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Abbreviations
- ADCC:
-
Antibody-dependent cell-mediated cytotoxicity
- BrdU:
-
Bromodeoxyuridine
- CD56:
-
NCAM1, Neural cell adhesion molecule 1
- DMSO:
-
Dimethyl sulfoxide
- FBS:
-
Fetal bovine serum
- IL-2:
-
Interleukin-2 protein
- IL-2R:
-
Interleukin-2 receptor
- LLT1:
-
Lectin-like transcript 1
- mAb:
-
Monoclonal antibody
- NK:
-
Natural killer cell
- NKSF:
-
NK cell stimulatory factor
- NKT:
-
Natural killer T cell
- PBMC:
-
Peripheral blood mononuclear cells
- SD:
-
Standard deviation
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D. Zhu and L. G. Corral contributed equally to this study.
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Zhu, D., Corral, L.G., Fleming, Y.W. et al. Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother 57, 1849–1859 (2008). https://doi.org/10.1007/s00262-008-0512-7
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DOI: https://doi.org/10.1007/s00262-008-0512-7