Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008.

Abstract

BACKGROUND:

Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL.

METHODS AND RESULTS:

Here, we report that Galectin-1 is expressed at different levels in and on different subclasses of BP-ALLs. Bone marrow plasma also contains high levels of Galectin-1. PTX008 is an allosteric inhibitor which inhibits Galectin-1 but not Galectin-3-mediated agglutination. The compound reduces migration of BP-ALL cells to CXCL12 and OP9 stromal cells and inhibits fibronectin-mediated adhesion. It also affects cell cycle progression of BCP-ALL cells. PTX008 is cytostatic for BP-ALL cells even when these are co-cultured with protective stroma, and can sensitize ALL cells to vincristine chemotherapy in vitro and in mice.

CONCLUSIONS:

PTX008 inhibits multiple functions that contribute to BP-ALL survival. The effects of Galectin-1 inhibition on both BP-ALL cell proliferation and migration suggest both the leukemia cells as well as the microenvironment that protects these cells may be targeted.

• Authors: Helicia Paz, Eun Ji Joo, Chih-Hsing Chou, Fei Fei, Kevin H Mayo, Hisham Abdel-Azim, Haike Ghazarian, John Groffen, Nora Heisterkamp
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 37 Issue 1 Pg. 67 (Mar 27 2018) ISSN: 1756-9966 [Electronic] England
• PMID: 29580262 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Galectin 1

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Adhesion (genetics)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Coculture Techniques
• Disease Models, Animal
• Galectin 1 (antagonists & inhibitors, genetics, metabolism)
• Gene Expression
• Humans
• Mice
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Protein Binding
• Xenograft Model Antitumor Assays