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

被引：6

作者：

Godbole, Abhijit M. ^{[1
,2
]}

Ramalingam, Senthilmurugan ^{[1
,2
]}

Ramamurthy, Vidya P. ^{[1
,2
]}

Khandelwal, Aakanksha ^{[1
]}

Bruno, Robert D. ^{[1
]}

Upreti, Vijay V. ^{[4
]}

Gediya, Lalji K. ^{[1
,2
]}

Purushottamachar, Puranik ^{[1
,2
]}

Mbatia, Hannah W. ^{[1
,2
]}

Addya, Sankar ^{[6
]}

Ambulos, Nicholas ^{[5
]}

Njar, Vincent C. O. ^{[1
,2
,3
]}

机构：

[1] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Med, Ctr Biomol Therapeut, Baltimore, MD 21201 USA

[3] Univ Maryland, Sch Med, Marlene Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA

[4] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

[5] Univ Maryland, Sch Med, Genom Core Facil, Baltimore, MD 21201 USA

[6] Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2014年 / 734卷

基金：

美国国家卫生研究院;

关键词：

RAMBA-VH/14-1; LTLC; Pharmacokinetics (PK); Breast cancer; ER stress; Autophagy; METABOLISM BLOCKING-AGENTS; RECEPTOR ANTAGONIST SB-265123; DOUBLE-EDGED-SWORD; ENDOPLASMIC-RETICULUM; MURINE TOXICOLOGY; GROWTH; BIOAVAILABILITY; RESISTANCE; INHIBITORS; POTENT;

D O I：

10.1016/j.ejphar.2014.04.004

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

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 (C-max) within 0.17 h 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 abreast cancer. (C) 2014 Elsevier By. All rights reserved.

引用

页码：98 / 104

页数：7

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