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: Abhijit M Godbole, Senthilmurugan Ramalingam, Vidya P Ramamurthy, Aakanksha Khandelwal, Robert D Bruno, Vijay V Upreti, Lalji K Gediya, Puranik Purushottamachar, Hannah W Mbatia, Sankar Addya, Nicholas Ambulos, Vincent C O Njar
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 734 Pg. 98-104 (Jul 05 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24726842 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• 4-(1H-imidazol-1-yl)retinoic acid
• Antineoplastic Agents
• Imidazoles
• Tretinoin
• Thapsigargin

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Autophagy (drug effects)
• Biological Availability
• Breast Neoplasms (pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Female
• Humans
• Imidazoles (administration & dosage, pharmacokinetics, pharmacology)
• Intracellular Space (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Thapsigargin (pharmacology)
• Tretinoin (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays