Accession Number : AD1046027


Title :   Development of a Synthetic Lethal Drug Combination That Targets the Energy Generation Triangle for Liver Cancer Therapy


Descriptive Note : Technical Report,01 Jun 2016,31 May 2017


Corporate Author : University of California, Los Angeles Los Angeles United States


Personal Author(s) : Xu, Shili


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1046027.pdf


Report Date : 01 Sep 2017


Pagination or Media Count : 11


Abstract : Metabolic reprogramming in HCC promotes cancer cell survival and growth. This reprograming also suggests possibilities to identify as yet unexplored therapeutic targets. While most normal tissues use HK1 for glycolysis, HK4 is the only HK isoform in hepatocytes. The transition from hepatocyte to HCC is frequently accompanied by a complete switch from HK4 to the highly active HK2 isoform, and increased glycolysis (the Warburg effect). HK2 gene deletion in adult mice does not significantly affect normal tissues; however, HK2 inhibition in HCC is cytostatic. Our high throughput screen (HTC) discovered diphenyleneiodonium (DPI) as a synthetic lethal partner that, in combination with HK2 inhibition, kills HCC cells through its inhibition of mitochondrial complex I. The combination of HK2 inhibition with DPI shifts fatty acid (FA) metabolism from FA synthesis to FA oxidation (FAO) in HCC cells to compensate energy loss. Compared to normal liver, HCC up-regulates expression of genes involved in FA biosynthesis and down-regulates expression of genes involved in FAO. Perhexiline (PER), a FAO inhibitor in clinical use, sensitizes HCC cells to HK2 inhibition/DPI-induced toxicity. In contrast, the HK2 inhibition/DPI/PER combination does not cause significant cytotoxicity in cells from other cancers (e.g., breast, lung, colon), suggesting this therapy will be tolerated in vivo. In this study, we developed a triple combination of HK2 inhibition, DPI, and PER to target the energy generation triangle (glycolysis, oxidative phosphorylation, and FAO) as a translational, effective and safe therapy for HCC.


Descriptors :   carcinomas , glycolysis , fatty acids , oxidation , mitochondria , drugs , metabolism , genes , inhibition , liver , cancer , cell line


Subject Categories : Medicine and Medical Research
      Anatomy and Physiology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE