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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.
Int J Oncol. 2010 Oct; 37(4):1023-30.IJ

Abstract

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.

Authors+Show Affiliations

GTx Inc., Memphis, TN 38163, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20811725

Citation

Li, Chien-Ming, et al. "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." International Journal of Oncology, vol. 37, no. 4, 2010, pp. 1023-30.
Li CM, Narayanan R, Lu Y, et al. 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. Int J Oncol. 2010;37(4):1023-30.
Li, C. M., Narayanan, R., Lu, Y., Hurh, E., Coss, C. C., Barrett, C. M., Miller, D. D., & Dalton, J. T. (2010). 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. International Journal of Oncology, 37(4), 1023-30.
Li CM, et al. 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. Int J Oncol. 2010;37(4):1023-30. PubMed PMID: 20811725.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Li,Chien-Ming, AU - Narayanan,Ramesh, AU - Lu,Yan, AU - Hurh,Eunju, AU - Coss,Christopher C, AU - Barrett,Christina M, AU - Miller,Duane D, AU - Dalton,James T, PY - 2010/9/3/entrez PY - 2010/9/3/pubmed PY - 2010/12/25/medline SP - 1023 EP - 30 JF - International journal of oncology JO - Int J Oncol VL - 37 IS - 4 N2 - 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. SN - 1791-2423 UR - https://www.unboundmedicine.com/medline/citation/20811725/2_Arylthiazolidine_4_carboxylic_acid_amides__ATCAA__target_dual_pathways_in_cancer_cells:_5'_AMP_activated_protein_kinase__AMPK_/mTOR_and_PI3K/Akt/mTOR_pathways_ L2 - http://www.spandidos-publications.com/ijo/37/4/1023 DB - PRIME DP - Unbound Medicine ER -