FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells.

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.

Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy.

Non-apoptotic forms of programmed cell death are targets for novel approaches in anticancer therapy. Indeed, cancer cells often present with mutations in the apoptotic machinery that result in resistance to most anticancer therapies and contribute to a relatively low response rate to therapies based on the use of pro-apoptotic strategies. (Macro-)autophagy can be a highly efficient mode of cell death induction by excessive self-digestion as demonstrated by our experiments that studied the effect of radiation to induce autophagy cell death in apoptosis-deficient cells. Despite current controversies on the possible role of autophagy in the process of carcinogenesis and cancer progression by promoting cell survival, autophagy can be seen as a backup cell death mechanism, when other cell death mechanisms fail. This review will focus on the pathways linking autophagy and cancer that are relevant for target identification and on pharmaceuticals that can be utilized to improve cancer therapy by targeting the autophagic pathway.