The Solution

Using a systems biology approach, we are attacking the metabolism of cancer cells on multiple levels.

Targeting Metabolic Dysfunction as a Strategy for Selective Cancer Apoptosis

  • Investigated long ago by Warburg (1956), the rate of anaerobic lactic acid production in cancer cells is much higher than in normal cells, however, it has recently been linked to a p53-dependent pathway [1].
  • It has been shown that p53 is involved in the modulation of glycolysis. Pyruvate, the major metabolic product of glycolysis, induces p53 expression [1].
  • Various enzymes involved in glycolysis are also regulated by p53. Type 2 hexokinase, an enzyme responsible for the conversion of glucose to glucose-6-phosphate during the initial reaction of glycolysis, is up regulated by p53 [2]. It has also been shown that this enzyme possesses a p53 response element in the promoter region of its gene [3].
  • Hypoxia which induces p53 expression also induces type 2 hexokinase [4]. Phosphoglycerate mutase, another enzyme involved in the glycolysis which converts 3-phosphoglycerate to 2-phosphoglycerate during the late stage of glycolysis, is negatively regulated by p53.
  • TP53-induced glycolysis and apoptosis regulator (TIGAR) has recently been discovered to connect p53 with glucose metabolism [5]. TIGAR is similar to proteins of the phosphoglycerate mutase family and shares similarity with bisphosphatase domain of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase [6]. An increase in TIGARexpression results in a decrease in fructose-2, 6-bisphosphatase levels to blunt glycolytic flux. TIGARalso decreases the cellular levels of reactive oxygen species (ROS) during mild cellular stress. Interestingly, ROS can upregulatep53 transcriptional activity thus providing a feedback loop. This mechanism is significant during hypoxic conditions where ROS are required to partially mediate the effects of radiation and anti-cancer drugs [7].
  • In addition to regulating the proteins involved in mitochondrial apoptotic pathway (intransic) such as Bac, Bcl-2 and PUMA, p53 is considered important in regulating the translocation of proteins localized to the outer surface of mitochondria thus regulating mitochondrial membrane potential [8]. These differences in the energy metabolism of p53 deficient and proficient cells provide a therapeutic opportunity to target specifically p53 deficient cells.

Proposed Mechanism of Action

  • ATI01 is involved in regulating intracellular H+ levels and reactivation of the TCA aerobic metabolism cycle that often occur in ischemic conditions seen in PAD/CLI and drives anerobic metabolism to aerobic metabolism.
  • Cancer cells are highly metabolically active and consume more oxygen than is available and produce heavy levels of lactic acid which mimic anerobic metabolism.
  • It has been shown that p53 is involved in the modulation of glycolysis that occurs in aerobic metabolism and not in anerobic metabolism. Pyruvate, the major metabolic product of glycolysis, induces p53 expression.
  • We believe ATI01 is modulating or influencing the TIGAR regulator protein.
  • ATI01 contributes to the regulations of the mitochondrial membrane and should assist in inducing p53 activity.

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[2]. Cheung EC, VousdenKH. The role of p53 in glucose metabolism. CurrOpinCell Biol. 2010; 22(2):186–91. [PubMed: 20061129]

[3]. MalthupalaSP, HeeseC, Pedersen PL. Glucose catabolism in can-cercells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J Biol Chem. 1997; 272(36):22776–80. [PubMed: 9278438]

[4]. YalcinA, TelangS, Clem B, Chesney J. Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatases in cancer. Exp Mol Pathol. 2009; 86(3): 174–9. [PubMed: 19454274]

[5]. BensaadK, Tsuruta A, SelakMA, Vidal MN, Nakano K, BartronsR, Gottlieb E, VousdenKH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006; 126(1):107–20. [PubMed: 16839880]

[6]. SalminenA, KaamirantaK. Glycolysis links p53 function with NF-kappaBsignaling: impact on cancer and aging process. J Cell Physiol. 2010; 224(1):1–6. [PubMed: 20301205]

[7]. BensaadK, Cheung EC, VousdenKH. Modulation of intracellular ROS levels by TIGARcontrols autophagy. EMBOJ. 2009; 28(19):3015–26. [PubMed: 19713938]

[8]. Han J, Goldstein LA, Hou W, GastmanBR, RabinowichH. Regu-lationof mitochondrial apoptotic events by p63-mediated disrup-tionof complexes between antiapoptotic Bcl-2 members and Bim. J Biol Chem. 2010; 285(29):22473–83. [PubMed: 20404322]