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FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells. Surgery 2017 Mar;161(3):747-752

Date

12/07/2016

Pubmed ID

27919448

Pubmed Central ID

PMC5369647

DOI

10.1016/j.surg.2016.09.009

Scopus ID

2-s2.0-85007492121 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

BACKGROUND: The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells.

METHODS: We surveyed 3 MYCN-single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis.

RESULTS: LDHA is frequently expressed in both MYCN--amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN-single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis.

CONCLUSION: Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas.

Author List

Rellinger EJ, Craig BT, Alvarez AL, Dusek HL, Kim KW, Qiao J, Chung DH

Author

Brian T. Craig MD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Apoptosis
Cell Culture Techniques
Cell Cycle
Cell Line, Tumor
Cell Survival
Glycolysis
Humans
N-Myc Proto-Oncogene Protein
Naphthalenes
Neuroblastoma
Proto-Oncogene Proteins c-myc