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

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• 作者：Abhijit M. Godbole^a ; ^b ; ¹ ; ² ; Senthilmurugan Ramalingam^a ; ^b ; ¹ ; Vidya P. Ramamurthy^a ; ^b ; ¹ ; Aakanksha Khandelwal^a ; ³ ; Robert D. Bruno^a ; ⁴ ; Vijay V. Upreti^d ; ⁵ ; Lalji K. Gediya^a ; ^b ; Puranik Purushottamachar^a ; ^b ; Hannah W. Mbatia^a ; ^b ; Sankar Addya^f ; Nicholas Ambulos^e ; Vincent C.O. Njar^a ; ^b ; ^c ; ^{vnjar@som.umaryland.edu" class="auth_mail}
• 关键词：RAMBA-VN/14-1 ; LTLC ; Pharmacokinetics (PK) ; Breast cancer ; ER stress ; Autophagy
• 刊名：European Journal of Pharmacology
• 出版年：5 July 2014
• 年：2014
• 卷：734
• 期：Complete
• 页码：98-104
• 全文大小：1041 K

文摘

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 of breast cancer.