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Axitinib targeted cancer stemlike cells to enhance efficacy of chemotherapeutic drugs via inhibiting the drug transport function of ABCG2.

Abstract
Stemlike cells have been isolated by their ability to efflux Hoechst 33342 dye and are called the side population (SP). We evaluated the effect of axitinib on targeting cancer stemlike cells and enhancing the efficacy of chemotherapeutical agents. We found that axitinib enhanced the cytotoxicity of topotecan and mitoxantrone in SP cells sorted from human lung cancer A549 cells and increased cell apoptosis induced by chemotherapeutical agents. Moreover, axitinib particularly inhibited the function of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) and reversed ABCG2-mediated multidrug resistance (MDR) in vitro. However, no significant reversal effect was observed in ABCB1-, ABCC1- or lung resistance-related protein (LRP)-mediated MDR. Furthermore, in both sensitive and MDR cancer cells axitinib neither altered the expression of ABCG2 at the mRNA or protein levels nor blocked the phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2. In nude mice bearing ABCG2-overexpressing S1-M1-80 xenografts, axitinib significantly enhanced the antitumor activity of topotecan without causing additional toxicity. Taken together, these data suggest that axitinib particularly targets cancer stemlike cells and reverses ABCG2-mediated drug resistance by inhibiting the transporter activity of ABCG2.
AuthorsFang Wang, Yan-jun Mi, Xing-Gui Chen, Xing-ping Wu, Zhenguo Liu, Shu-peng Chen, Yong-ju Liang, Chao Cheng, Kenneth Kin Wah To, Li-wu Fu
JournalMolecular medicine (Cambridge, Mass.) (Mol Med) Vol. 18 Pg. 887-98 ( 2012) ISSN: 1528-3658 [Electronic] United States
PMID22549112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCG2 protein, human
  • Antineoplastic Agents
  • Imidazoles
  • Indazoles
  • Neoplasm Proteins
  • axitinib
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
Topics
  • ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, metabolism)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Biological Transport (drug effects)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm (genetics)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Imidazoles (pharmacology)
  • Indazoles (pharmacology)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
  • Neoplasms (genetics, metabolism)
  • Neoplastic Stem Cells (drug effects, metabolism)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Xenograft Model Antitumor Assays

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