Selective targeting of FAK-Pyk2 axis by alpha-naphthoflavone abrogates doxorubicin resistance in breast cancer cells.

Abstract

Despite an initial positive response, breast cancer cells inevitably acquire resistance to doxorubicin (Dox). Alpha-naphthoflavone (ANF) is a well-known chemopreventive agent; however, its anti-cancer properties have not been established. We examined the therapeutic efficacy of ANF in doxorubicin-resistant MCF-7 (MCF-7/Dox) breast cancer cells and investigated its underlying molecular mechanisms of action. MCF-7/Dox cells expressed constitutively active forms of the tyrosine kinases: focal adhesion kinase (FAK-Y397) and protein tyrosine kinase 2 beta (Pyk2- Y579/580) compared with parental MCF-7 cells. ANF significantly enhanced the sensitivity of MCF-7/Dox cells to Dox cytotoxicity in vitro and when co-administered in vivo. This ANF-mediated chemosensitization has dual mechanisms of action: (a) intracellular Dox retention via suppression of P-glycoprotein pump activity, and (b) inhibition of clonogenic cell survival via de-phosphorylation of FAK, Pyk2, and EGF-induced Akt in MCF-7/Dox cells and tumor xenografts. Because of its strong chemosensitization action, broad safety profile, and health benefits, ANF is an attractive anti-cancer drug with therapeutic implications to circumvent drug resistance in breast cancer patients.

• Authors: Amrita Datta, Nobel Bhasin, Hogyoung Kim, Manish Ranjan, Barbara Rider, Zakaria Y Abd Elmageed, Debasis Mondal, Krishna C Agrawal, Asim B Abdel-Mageed
• Journal: Cancer letters (Cancer Lett) Vol. 362 Issue 1 Pg. 25-35 (Jun 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25796439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Benzoflavones
• Protein Kinase Inhibitors
• alpha-naphthoflavone
• Doxorubicin
• Focal Adhesion Kinase 1
• Focal Adhesion Kinase 2
• PTK2 protein, human

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzoflavones (administration & dosage, pharmacology)
• Breast Neoplasms (drug therapy, enzymology)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Focal Adhesion Kinase 1 (antagonists & inhibitors, metabolism)
• Focal Adhesion Kinase 2 (antagonists & inhibitors, metabolism)
• Humans
• MCF-7 Cells
• Mice
• Mice, Nude
• Molecular Targeted Therapy
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays