Treatment with the C-C chemokine receptor type 5 (CCR5)-inhibitor maraviroc suppresses growth and induces apoptosis of acute lymphoblastic leukemia cells

摘要

Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy diagnosed in children and is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. C-C chemokine receptor type 5 (CCR5) is a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. A highly potent competitive antagonist of CCR5, maraviroc, recently has been identified with suppression of cancer cells aggressive in a variety of cancers. However, the effects of maraviroc on ALL cells have not yet been defined. Here we report that CCR5 selective inhibitor significantly inhibited ALL cells SUP-B15 growth and induced SUP-B15 cells to undergo cell apoptosis. This cell apoptosis was associated with increased levels of cleavage of caspase-3 and caspase-9, and Poly (ADP-ribose) polymerase (PARP). Moreover, we demonstrated that maraviroc strongly inhibited SUP-B15 cells migration to C-X-C motif chemokine ligand 12 (CXCL12) and CXCL13, and adhesion to fibronectin and vascular cell adhesion molecule 1 (VCAM-1) in vitro. Importantly, CCR5-activated signaling proteins Janus Kinase 1 (JAK1), JAK2 and signal transducer and activator of transcription (STAT3) were inhibited by maraviroc. Finally, maraviroc suppressed the growth of SUP-B15 xenograft tumors in athymic mice. Collectively, this study demonstrated that CCR5 inhibition by maraviroc has the potential for the treatment of human ALL.