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

Hejing Huang1, Huanan Liu2, Changmei Liu2

  • 1Department 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.

Cancer Letters
|February 28, 2015
PubMed

Insights

A novel compound, 17#, inhibits the unfolded protein response (UPR) to selectively target cancer cells. This UPR inhibition shows therapeutic potential and enhances sensitivity to existing chemotherapy drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cancer cells face endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR) for survival.
  • Developing selective chemotherapy agents targeting cancer-specific adaptive mechanisms remains a challenge.

Purpose of the Study:

  • To identify and characterize a novel small-molecule compound that inhibits the UPR.
  • To evaluate the anti-cancer efficacy and selectivity of this compound, alone and in combination with other agents.
  • To elucidate the molecular mechanisms underlying the compound's anti-cancer effects.

Main Methods:

  • Discovery of a novel small-molecule compound, designated 17#.
  • In vitro evaluation of 17# for growth inhibition in cancer cells under glucose deprivation (mimicked by 2-deoxy-D-glucose, 2DG).
  • In vivo studies using HeLa tumor xenografts to assess the anti-cancer effects of 17# and its combination with 2DG.
  • Mechanistic studies involving gene overexpression (GRP78, XBP1s) to investigate the role of UPR inhibition.
  • Assessment of 17# in combination with established chemotherapy drugs (doxorubicin, etoposide) to evaluate drug sensitivity modulation.

Main Results:

  • Compound 17# was identified as a potent pan-UPR inhibitor.
  • 17# demonstrated selective growth inhibition of cancer cells under glucose-deprived conditions.
  • 17# showed mild suppression of tumor xenograft growth and synergistic effects with 2DG.
  • UPR inhibition by 17# was crucial for its selective anti-cancer effects, with GRP78 or XBP1s overexpression partially reversing these effects.
  • 17# enhanced the sensitivity of cancer cells to doxorubicin and etoposide.

Conclusions:

  • Disrupting the unfolded protein response (UPR) presents a viable strategy for selective cancer therapy.
  • The novel compound 17# exhibits therapeutic potential by inhibiting UPR and enhancing drug sensitivity.
  • Targeting UPR offers a promising avenue for developing novel anti-cancer treatments and overcoming drug resistance.
Keywords:
2DGSelective cancer therapyUPR disrupterUnfolded protein response

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