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Cancer Lett. 2015 May 1;360(2):257-68. doi: 10.1016/j.canlet.2015.02.029. Epub 2015 Feb 23.

Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth.

Author information

1
Department of Hematology, Changzheng Hospital, Second Military Medical University, Shanghai 201203, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
2
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ybzhou@simm.ac.cn.
4
Department of Hematology, Changzheng Hospital, Second Military Medical University, Shanghai 201203, China.

Abstract

Identifying chemotherapy candidates with high selectivity against cancer cells is a major challenge in cancer treatment. Tumor microenvironments cause chronic endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) as an adaptive response. Here, one novel small-molecule compound, 17#, was discovered as a potent pan-UPR inhibitor. It exhibited good selection for growth inhibition when cancer cells were cultured in 2-deoxy-D-glucose (2DG), mimicking an in vitro glucose-deprived status. Additionally, 17# alone could mildly suppress the growth of HeLa tumor xenografts, and a synergistic anti-cancer effect was observed when 17# was combined with 2DG. A mechanistic study showed that 17#-induced selective anti-cancer effects were highly dependent on UPR inhibition, and overexpressing GRP78 or XBP1s reversed the 17#-induced growth inhibition and cell cycle arrest, partially by delaying the downregulation of the cell cycle regulator cyclin B1. Furthermore, 17# improved the sensitivity of anti-cancer drugs such as doxorubicin or etoposide. Our study presents evidence that disrupting the UPR has selective therapeutic potential and may enhance drug sensitivity.

KEYWORDS:

2DG; Selective cancer therapy; UPR disrupter; Unfolded protein response

PMID:
25721085
DOI:
10.1016/j.canlet.2015.02.029
[Indexed for MEDLINE]

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