title: Antitumor activity of NRC-AN-019 in a pre-clinical breast cancer model.
abstract: Breast cancer is the second most frequently diagnosed tumor in women. Overexpression of human epidermal growth factor receptors (EGFRs) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior and response to systemic therapy. In this study, we describe a novel compound (NRC-AN-019), which has better antitumor activity than Lapatinib. Here, we demonstrate that NRC-AN-019 is more effective in inhibiting angiogenic potential and proliferation of both MDAMB231 and HTB20/BT474 cells. FACS analysis shows that NRC-AN-019 treatment caused the accumulation of MDAMB231 and BT474 cells in the sub G0/1 phase in a dose-dependent manner and was accompanied by increased PARP cleavage, which is indicative of apoptosis. In addition, we observed inhibition of EGFR phosphorylation in both MDAMB231 and BT474 cells. From our animal studies using SCID mice implanted with BT474 cells, we observed dose-dependent inhibition of tumor growth in NRC-AN-019-treated animals compared to controls or Lapatinib-treated mice at comparable concentrations. The dose-dependent inhibition of EGFR phosphorylation was confirmed by immunohistochemical analysis of tumor sections. In vitro results demonstrate that NRC-AN-019 is superior to Lapatinib in EGFR-overexpressing cells and has strong anti-angiogenic, anti-proliferative and pro-apoptotic properties in an EGFR-overexpressing background (BT474). In vivo studies demonstrate that the antitumor activity of NRC-AN-019 is better over Lapatinib. These results suggest that NRC-AN-019 has greater therapeutic potential in the treatment of Her-2-positive breast cancer.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Gondi
authors.forename: Bharathi
authors.initials: B
authors.lastname: Gorantla
authors.forename: A K S
authors.initials: AK
authors.lastname: Bhujanga Rao
authors.forename: K
authors.initials: K
authors.lastname: Amala
authors.forename: M U R
authors.initials: MU
authors.lastname: Naidu
authors.forename: K V
authors.initials: KV
authors.lastname: Jogi
authors.forename: G
authors.initials: G
authors.lastname: Venkat Ramana
authors.forename: Praveen C
authors.initials: PC
authors.lastname: Myneni
authors.forename: Ajit
authors.initials: A
authors.lastname: Junnarkar
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib