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  • Title: The combination of proteasome inhibitors bortezomib and gambogic acid triggers synergistic cytotoxicity in vitro but not in vivo.
    Author: Liu N, Huang H, Xu L, Hua X, Li X, Liu S, Yang C, Zhao C, Zhao C, Li S, Dou QP, Liu J.
    Journal: Toxicol Lett; 2014 Jan 30; 224(3):333-40. PubMed ID: 24291039.
    Abstract:
    The proteasome inhibitor-based combinational therapy has been reported to be an efficient cancer treatment. Our recent studies demonstrated that the natural compound gambogic acid (GA) is a tissue-specific proteasome inhibitor, comparable to bortezomib (Bor), and sensitizes malignant cells to the proteasome inhibitor MG132/MG262 both in vitro and in vivo. The aim of this study was to further extend our investigation by combining GA with the clinically used proteasome inhibitor Bor to test their combined efficacy against human hepatoma HepG2 and mouse hepatoma H22 cells. GA and Bor synergistically induced cytotoxicity and cell death in human HepG2 and mouse H22 cells, and accelerated proteasome inhibition, endoplasmic reticulum (ER) stress and caspase activation in HepG2 cancer cells. However, unexpectedly, GA did not enhance or even antagonized Bor-induced tumor growth inhibition in H22 allograft and HepG2 xenograft tumor models. These findings demonstrated that GA increased Bor activity in vitro but limited the efficacy of Bor in vivo. We suggest that the combination of GA and Bor be avoided when administering these drugs to patients.
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