title: 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: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA; Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Amrita
authors: A
authors: Datta
authors: Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Nobel
authors: N
authors: Bhasin
authors: Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Hogyoung
authors: H
authors: Kim
authors: Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Manish
authors: M
authors: Ranjan
authors: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Barbara
authors: B
authors: Rider
authors: Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Zakaria Y
authors: ZY
authors: Abd Elmageed
authors: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Debasis
authors: D
authors: Mondal
authors: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA.
authors: Krishna C
authors: KC
authors: Agrawal
authors: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA; Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA. Electronic address: amageed@tulane.edu.
authors: Asim B
authors: AB
authors: Abdel-Mageed
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001571:Benzoflavones / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001571:Benzoflavones; D047428:Protein Kinase Inhibitors; C011512:alpha-naphthoflavone; D004317:Doxorubicin; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human
keywords: Breast cancer; Chemotherapeutic resistance; Doxorubicin; Focal adhesion kinase; α-Naphthoflavone