title: Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation.
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.
authors.affiliation: Celgene Corporation, 4550 Towne Centre Court, San Diego, CA, 92121, USA. dzhu@celgene.com
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.forename: Yuedi W
authors.initials: YW
authors.lastname: Fleming
authors.forename: Bernd
authors.initials: B
authors.lastname: Stein
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D000077269:Lenalidomide; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; C467566:pomalidomide; D000077269:Lenalidomide