title: Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells.
abstract: Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found that GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting that GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: pruvolo@mdanderson.org.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Benton
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: AlRawi
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jared K
authors.initials: JK
authors.lastname: Burks
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Schober
authors.affiliation: La Jolla Pharmaceutical Company, San Diego, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Rolke
authors.affiliation: La Jolla Pharmaceutical Company, San Diego, CA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tidmarsh
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Numsen
authors.initials: N
authors.lastname: Hail
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D037161:Galectins / Q000037:antagonists & inhibitors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011134:Polysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C505531:GCS-100; D037161:Galectins; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011134:Polysaccharides; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C579720:venetoclax
keywords: GCS-100; Galectin; Leukemia; MCL-1; Signal transduction; p53