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

ABSTRACT: 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.

SUBMITTER: Zi J

PROVIDER: S-EPMC5411794 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Zi Jie J Yuan Shushu S Qiao Jianlin J Zhao Kai K Xu Linyan L Qi Kunming K Xu Kailin K Zeng Lingyu L

American journal of cancer research 20170401 4

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. Ho ...[more]

PMID: 28469959

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Project description:T‑cell acute lymphoblastic leukemia (T‑ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T‑cell progenitors. Conventional treatments for T‑ALL fail to prevent or cure the disease, with a high‑risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T‑ALL. Niclosamide, a traditional oral anti‑helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T‑ALL. Here, the present study aimed to investigate the anti‑leukemia effects of niclosamide on T‑ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T‑ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T‑ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T‑ALL cells treated with niclosamide, changes in apoptosis‑ and autophagy‑related proteins were analyzed by western blotting. In addition, in an in vivo model, T‑ALL xenograft mice were used to study the anti‑leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF‑CEM T‑ALL cells in both a dose‑ and time‑dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF‑CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase‑3 and LC3B, while downregulated those of Bcl‑2 and p62, in a dose‑dependent manner in both Jurkat and CCRF‑CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T‑ALL xenograft mice by activating cleaved caspase‑3 and LC3B. We conclude that niclosamide plays an anti‑leukemia role, and that it represents a novel approach for the treatment of T‑ALL.

Dataset Information

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

Publications

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

Similar Datasets

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