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Periplocin and cardiac glycosides suppress the unfolded protein response

Muneshige Tokugawa1, Yasumichi Inoue2,3, Kan'ichiro Ishiuchi4

  • 1Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.

Scientific Reports
|May 5, 2021
PubMed

Insights

Myanmar wild plant extracts were screened for compounds that suppress the unfolded protein response (UPR). Periplocin, a cardiac glycoside, was identified as a potent UPR inhibitor, showing promise for understanding UPR-related diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The unfolded protein response (UPR) is crucial for maintaining protein homeostasis.
  • Dysregulation of UPR signaling is implicated in various human diseases.
  • Modulators of UPR offer potential therapeutic insights.

Purpose of the Study:

  • To screen for small-molecule compounds that suppress UPR using Myanmar wild plant extracts.
  • To identify novel inhibitors of UPR pathways.
  • To investigate the therapeutic potential of identified compounds in diseases associated with UPR dysregulation.

Main Methods:

  • Screening of Myanmar wild plant extracts for UPR suppressive activity.
  • Utilizing a system to track X-box binding protein 1 (XBP1) splicing.
  • Isolation and identification of active compounds, including periplocin.
  • Assessing the effects of periplocin on different UPR axes (IRE1-XBP1, PERK, ATF6).
  • Evaluating structure-activity relationships of periplocin and related cardiac glycosides.
  • Testing the cytotoxic effects of periplocin on human multiple myeloma cell lines.

Main Results:

  • The ethanol extract of Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway.
  • Periplocin was isolated and identified as a potent inhibitor of the IRE1-XBP1 axis.
  • Periplocin also suppressed the PERK and ATF6 UPR pathways.
  • Cardiac glycosides, including periplocin, were found to inhibit UPR.
  • Periplocin demonstrated cytotoxic effects on human multiple myeloma cell lines (AMO1 and RPMI8226) by suppressing constitutive XBP1 activation.

Conclusions:

  • Periplocin and other cardiac glycosides represent novel suppressors of UPR.
  • These findings provide new molecular insights into UPR regulation.
  • Periplocin's ability to suppress UPR and exert cytotoxic effects suggests its potential in treating UPR-associated pathologies, such as multiple myeloma.

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