Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation

Cancer Immunol Immunother. 2008 Dec;57(12):1849-59. doi: 10.1007/s00262-008-0512-7. Epub 2008 Apr 8.

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.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Coculture Techniques
  • Drug Screening Assays, Antitumor / methods
  • Flow Cytometry
  • Humans
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Lenalidomide
  • Leukocytes, Mononuclear / immunology
  • Lymphoma, Non-Hodgkin / immunology
  • Male
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Prostatic Neoplasms / immunology
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology

Substances

  • Antineoplastic Agents
  • Thalidomide
  • pomalidomide
  • Lenalidomide