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

Cancer Letters
Amrita DattaAsim B Abdel-Mageed

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.

References

Apr 1, 1983·Biochemical Pharmacology·B Havsteen
Sep 7, 1984·Science·J T Kellis, L E Vickery
Jan 1, 1993·Annual Review of Biochemistry·M M Gottesman, I Pastan
Oct 9, 1996·Biochimica Et Biophysica Acta·I Bosch, J Croop
Oct 7, 1998·Chemical Research in Toxicology·T ShimadaF P Guengerich
Jul 27, 1999·Life Sciences·G Di CarloF Capasso
Mar 18, 2003·Journal of Cell Science·J Thomas Parsons
Dec 4, 2003·Environmental Health Perspectives·Shu ZhangStephen H Safe
Dec 17, 2003·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·H-S MoonS-C Kim
Apr 23, 2004·Molecular Pharmacology·Shuzhong ZhangMarilyn E Morris
Dec 9, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Liang ZhaoJessie L-S Au
Feb 1, 2005·Plant Foods for Human Nutrition·L H YaoS S Chen
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Satyajit K MitraDavid D Schlaepfer
Dec 21, 2005·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Christopher J EndresJashvant D Unadkat
Dec 27, 2005·Current Cancer Drug Targets·Lee Ann Cohen, Jun-Lin Guan
Mar 7, 2006·Nature Reviews. Drug Discovery·Gergely SzakácsMichael M Gottesman
Oct 26, 2006·Cell Biology and Toxicology·A BastW J F van der Vijgh
Jul 27, 2007·Cardiovascular Toxicology·Hernán Cortés-Funes, Cyntia Coronado
Jul 27, 2007·Cardiovascular Toxicology·Aalt BastWim J F Van der Vijgh
Nov 29, 2007·Bioorganic & Medicinal Chemistry·Samir YahiaouiAlbert-José Chulia
Apr 9, 2008·The Journal of Cell Biology·Sara M WeisDavid A Cheresh
Jul 26, 2008·Critical Reviews in Eukaryotic Gene Expression·Thomas A GasiewiczLoretta L Collins
Jul 9, 2009·Chemical Reviews·Paul D W Eckford, Frances J Sharom
Dec 17, 2009·Expert Opinion on Therapeutic Targets·Christopher A Lipinski, Joseph C Loftus
Dec 29, 2009·Frontiers in Bioscience (Elite Edition)·Liang ZhaoM Guillaume Wientjes
May 15, 2010·Expert Opinion on Investigational Drugs·Alexander Schultze, Walter Fiedler
Aug 15, 2012·Journal of Nutrition in Gerontology and Geriatrics·Donato F Romagnolo, Ornella I Selmin

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Citations

Aug 20, 2015·Journal of Cancer Research and Clinical Oncology·Paloma Silva de SouzaRaquel Ciuvalschi Maia
Jun 30, 2019·Critical Reviews in Microbiology·Rene Christena LowrenceSaisubramanian Nagarajan
Nov 21, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·N R CoelhoS A Pereira

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