CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy

Azab, Abdel Kareem; Runnels, Judith; Pitsillides, Costas; Moreau, Anne‐Sophie; Azab, Feda; Leleu, Xavier; Jia, Xiaoying; Wright, Renee D.; Ospina, Beatriz; Carlson, Adam; Alt, Clemens; Burwick, Nicholas; Roccaro, Aldo M.; Ngo, Hai T.; Farag, Mena; Melhem, Molly R.; Sacco, Antonio; Munshi, Nikhil C.; Hideshima, Teru; Rollins, Barrett J.; Anderson, Kenneth C.; Kung, Andrew L.; Lin, Charles P.; Ghobrial, Irène M.

doi:10.1182/blood-2008-10-186668

Cited by 385 publications

(394 citation statements)

References 40 publications

Supporting

Mentioning

373

Contrasting

Order By: Relevance

“…These data indicate the feasibility of using combinations of CXCR4 inhibitors and TKIs in CML and Ph( þ ) ALL. 13 Although this concept has already demonstrated improved therapeutic efficacy in the preclinical models of AML and multiple myeloma, 38,40,41 and has translated in the ongoing clinical trials, our findings indicate the alternative approach of lipid raft disruption to ameliorate microenvironmental resistance. The data presented here, indicate that lipid rafts facilitate key functional coupling between crosslinked CXCR4 and Lyn.…”

Section: Discussionmentioning

confidence: 99%

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

et al. 2011

View full text Add to dashboard Cite

We and others have previously demonstrated that p210 Bcr-Abl tyrosine kinase inhibits stromal cell-derived factor-1a/CXCR4 chemokine receptor signaling, contributing to the deficient adhesion of chronic myeloid leukemia (CML) cells to bone marrow stroma. Conversely, exposure of CML cells to a tyrosine kinase inhibitor (TKI) enhances migration of CML cells towards stromal cell layers and promotes non-pharmacological resistance to imatinib. Src-related kinase Lyn is known to interact with CXCL12/ CXCR4 signaling and is directly activated by p210 Bcr-Abl. In this study, we demonstrate that TKI treatment promoted CXCR4 redistribution into the lipid raft fraction, in which it co-localized with active phosphorylated form of Lyn (LynTyr396) in CML cells. Lyn inhibition or cholesterol depletion abrogated imatinib-induced migration, and dual Src/Abl kinase inhibitor dasatinib induced fewer CML cells to migrate to the stroma. These findings demonstrate the novel mechanism of microenvironmentmediated resistance through lipid raft modulation, which involves compartmental changes of the multivalent CXCR4 and Lyn complex. We propose that pharmacological targeting of lipid rafts may eliminate bone marrow-resident CML cells through interference with microenvironment-mediated resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

et al. 2011

View full text Add to dashboard Cite

show abstract

“…This suggests a clinical intervention in which mobilization of prostate cancer cells for the bone marrow microenvironment, as was done in the experimental models, could allow for sensitization of the prostate cancer cells to chemotherapy. Evidence for the effectiveness of this strategy in hematopoietic tumors has been demonstrated for both multiple myeloma 12 and acute myeloid leukemia 13 in which administration of AMD3100 induced their mobilization out of bone marrow and sensitized them to chemotherapy.…”

mentioning

confidence: 99%

Prostate cancer cells metastasize to the hematopoietic stem cell niche in bone

Keller¹

2011

Asian J Androl

View full text Add to dashboard Cite

“…68 Indeed, AMD3100 enhances the susceptibility to chemotherapy of acute myeloid leukemia 69 and multiple myeloma. 70 Recent clinical trials of adjuvant ZA have revealed that, when …”

Section: Discussionmentioning

confidence: 99%

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

Shiozawa¹,

Eber²,

Berry³

et al. 2015

BoneKEy Reports

View full text Add to dashboard Cite

Bone marrow is a heterogeneous organ containing diverse cell types, and it is a preferred metastatic site for several solid tumors such as breast and prostate cancer. Recently, it has been shown that bone metastatic cancer cells interact with the bone marrow microenvironment to survive and grow, and thus this microenvironment is referred to as the 'metastatic niche'. Once cancer cells spread to distant organs such as bone, the prognosis for the patient is generally poor. There is an urgent need to establish a greater understanding of the mechanisms whereby the bone marrow niche influences bone metastasis. Here we discuss insights into the contribution of the bone marrow 'metastatic niche' to progression of bone metastatic disease, with a particular focus on cells of hematopoietic and mesenchymal origin.

show abstract

CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy

Cited by 385 publications

References 40 publications

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

Prostate cancer cells metastasize to the hematopoietic stem cell niche in bone

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

Contact Info

Product

Resources

About