title: VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague Dawley rats.
abstract: Resistance to aromatase inhibitors is a major concern in the treatment of breast cancer. Long-term letrozole cultured (LTLC) cells represent a model of resistance to aromatase inhibitors. The LTLC cells were earlier generated by culturing MCF-7Ca, the MCF-7 human breast cancer cell line stably transfected with human placental aromatase gene for a prolonged period in the presence of letrozole. In the present study the effect of RAMBA, VN/14-1 on the sensitivity of LTLC cells upon multiple passaging and the mechanisms of action of VN/14-1 in such high passage LTLC (HP-LTLC) cells was investigated. We report that multiple passaging of LTLC cells (HP-LTLC cell clones) led to profound decrease in their sensitivity to VN/14-1. Additionally, microarray studies and protein analysis revealed that VN/14-1 induced marked endoplasmic reticulum (ER) stress and autophagy in HP-LTLC cells. We further report that VN/14-1 in combination with thapsigargin exhibited synergistic anti-cancer effect in HP-LTLC cells. Preliminary pharmacokinetics in rats revealed that VN/14-1 reached a peak plasma concentration (Cmax) within 0.17h after oral dosing. Its absolute oral bioavailability was >100%. Overall these results indicate potential of VN/14-1 for further clinical development as a potential oral agent for the treatment of breast cancer.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Abhijit M
authors.initials: AM
authors.lastname: Godbole
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Senthilmurugan
authors.initials: S
authors.lastname: Ramalingam
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Vidya P
authors.initials: VP
authors.lastname: Ramamurthy
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Khandelwal
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bruno
authors.affiliation: Department of Pharmaceutical sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Vijay V
authors.initials: VV
authors.lastname: Upreti
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Lalji K
authors.initials: LK
authors.lastname: Gediya
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Hannah W
authors.initials: HW
authors.lastname: Mbatia
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, PA 19107, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.affiliation: Genomic Core Facility, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ambulos
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA; Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA. Electronic address: vnjar@som.umaryland.edu.
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C496751:4-(1H-imidazol-1-yl)retinoic acid; D000970:Antineoplastic Agents; D007093:Imidazoles; D014212:Tretinoin; D019284:Thapsigargin
keywords: Autophagy; Breast cancer; ER stress; LTLC; Pharmacokinetics (PK); RAMBA-VN/14-1
references.citation: AAPS PharmSci. 2004 Jan 09;6(1):E1
references.pmid: 15198502
references.citation: Mini Rev Med Chem. 2002 Jun;2(3):261-9
references.pmid: 12370067
references.citation: Br J Cancer. 2011 Nov 22;105(11):1759-67
references.pmid: 22045189
references.citation: Cancer Biol Ther. 2011 Jan 15;11(2):127-37
references.pmid: 21178393
references.citation: Bioorg Med Chem. 2006 Jul 1;14(13):4323-40
references.pmid: 16530416
references.citation: Mol Cancer Ther. 2008 Sep;7(9):2828-36
references.pmid: 18790763
references.citation: Nature. 1999 Jan 21;397(6716):271-4
references.pmid: 9930704
references.citation: Xenobiotica. 2004 Apr;34(4):367-77
references.pmid: 15268981
references.citation: Autophagy. 2009 Apr;5(3):400-3
references.pmid: 19221464
references.citation: Cancer Res. 2006 Dec 1;66(23):11485-93
references.pmid: 17145897
references.citation: J Intern Med. 2010 Nov;268(5):410-8
references.pmid: 20964733
references.citation: FASEB J. 2005 Feb;19(2):240-2
references.pmid: 15545299
references.citation: Genes Dev. 1998 Apr 1;12(7):982-95
references.pmid: 9531536
references.citation: Cell Growth Differ. 1999 Apr;10(4):255-62
references.pmid: 10319995
references.citation: Biopharm Drug Dispos. 1999 Oct;20(7):347-54
references.pmid: 10760843
references.citation: Br J Cancer. 2007 Apr 23;96(8):1204-15
references.pmid: 17387344
references.citation: J Med Chem. 2007 Oct 4;50(20):4953-75
references.pmid: 17824681
references.citation: Cold Spring Harb Perspect Biol. 2011 Sep 01;3(9):a004424
references.pmid: 21813400
references.citation: Xenobiotica. 2004 Apr;34(4):353-66
references.pmid: 15268980
references.citation: Mol Cancer Ther. 2012 Apr;11(4):898-908
references.pmid: 22334589
references.citation: Nat Rev Drug Discov. 2007 Oct;6(10):793-810
references.pmid: 17906642
references.citation: Cancer Chemother Pharmacol. 2007 Nov;60(6):899-905
references.pmid: 17345084
references.citation: Sci Signal. 2010 Nov 09;3(147):ra81
references.pmid: 21062993
references.citation: Int J Cancer. 2009 Sep 1;125(5):991-5
references.pmid: 19452527
references.citation: Cancer Lett. 2011 Jan 28;300(2):105-14
references.pmid: 21036469
references.citation: Cancer Chemother Pharmacol. 2011 Apr;67(4):899-910
references.pmid: 20593179
references.citation: Clin Cancer Res. 2003 Jun;9(6):1980-9
references.pmid: 12796359
references.citation: Adv Ther. 2011 Dec;28(12):1045-58
references.pmid: 22068628
references.citation: Cancer Res. 2010 Jan 15;70(2):440-6
references.pmid: 20068163
references.citation: PLoS One. 2009 Jul 16;4(7):e6251
references.pmid: 19606230
references.citation: Cancer Chemother Pharmacol. 2012 Aug;70(2):339-44
references.pmid: 22580781
references.citation: J Steroid Biochem Mol Biol. 2012 Sep;131(3-5):83-92
references.pmid: 22265958
references.citation: J Med Chem. 2007 Aug 9;50(16):3825-40
references.pmid: 17616115
references.citation: Clin Cancer Res. 2009 Sep 1;15(17):5308-16
references.pmid: 19706824
references.citation: J Med Chem. 2004 Dec 30;47(27):6716-29
references.pmid: 15615521