2-Arylthiazolidine-4-carboxylic acid amides (ATCAA) target dual pathways in cancer cells: 5'-AMP-activated protein kinase (AMPK)/mTOR and PI3K/Akt/mTOR pathways.
Phosphatidylinositol-3-kinase (PI3K)/Akt and 5'-AMP-activated protein kinase (AMPK) are attractive targets for anti-cancer drug development. Inhibition of Akt or activation of AMPK is cytotoxic to human cancer cells in vitro and in vivo. We previously demonstrated that 2-arylthiazolidine-4-carboxylic acid amides (ATCAA) are effective cytotoxic agents in prostate and melanoma cancer cell lines, with IC(50) values in the low/sub micromolar range. Using in vitro and in vivo studies, we further characterized the anti-cancer efficacy and mechanism of action of ATCAA-10, a potent lead. ATCAA-10 exhibited equal potency on both MES/SA and P-glycoprotein over-expressing multidrug resistant MES/SA/Dx5 cells, suggesting that ATCAA-10 may overcome multiple drug resistance. Cell-free kinase binding assays excluded the direct binding of ATCAA-10 to several kinases, including IGF-1R, EGFR, FGFR and PDGFR. However, in A549 and HeLa cells, ATCAA-10 effectively dephosphorylated Akt, with concomitant phosphorylation of AMPK. Determination of intracellular ATP and AMP concentrations revealed that ATCAA-10 activated AMPK by altering the intracellular AMP/ATP ratio. ATCAA-10 exhibited favorable pharmacokinetic properties in both mice and rats, including low clearance, low hepatic extraction rate, moderate volume of distribution and long half-life. In addition, ATCAA-10 inhibited A549 tumor xenograft growth with 46% tumor growth inhibition (TGI) at 20 mg/kg dose. Taken together; these results suggest that ATCAA-10 modulates the activity of two signaling pathways, PI3K/AKT/mTOR and AMPK/mTOR, resulting in the inhibition of cancer cell growth.
Li
Chien-Ming
CM
GTx Inc., Memphis, TN 38163, USA.
Narayanan
Ramesh
R
Lu
Yan
Y
Hurh
Eunju
E
Coss
Christopher C
CC
Barrett
Christina M
CM
Miller
Duane D
DD
Dalton
James T
JT
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D053778:Thiazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D000577:Amides; D000970:Antineoplastic Agents; D001786:Blood Glucose; D002264:Carboxylic Acids; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D053778:Thiazolidines; C546842:MTOR protein, human