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ER stress-mediated autophagic cell death induction through methylated β-cyclodextrins-threaded acid-labile

Kei Nishida1, Atsushi Tamura1, Nobuhiko Yui1

  • 1Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|February 12, 2018
PubMed

Insights

Methylated β-cyclodextrins (Me-β-CDs) released from acid-labile polyrotaxane (Me-PRX) induce endoplasmic reticulum (ER) stress and autophagy. This Me-PRX effectively triggers autophagic cell death, even in apoptosis-resistant cancer cells.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Nanomedicine

Background:

  • Autophagy is crucial in disease development and prevention.
  • Inducing autophagy offers a therapeutic strategy for intractable diseases.
  • Methylated β-cyclodextrins (Me-β-CDs) are investigated for their biological effects.

Purpose of the Study:

  • To investigate the induction of autophagy by Me-β-CDs released from an acid-labile polyrotaxane (Me-PRX).
  • To explore the potential of Me-PRX as a therapeutic agent for inducing cell death, particularly in apoptosis-resistant cancers.

Main Methods:

  • Me-PRX was designed to release Me-β-CDs in response to acidic lysosomal pH.
  • Endoplasmic reticulum (ER) stress was assessed via gene expression and protein markers.
  • Autophagy induction and cell death were evaluated in cells treated with Me-PRX and control substances.

Main Results:

  • Me-PRX preferentially accumulated in the ER, inducing significant ER stress.
  • Autophagy was observed in cells treated with Me-PRX, but not with non-labile controls or free Me-β-CDs.
  • Me-PRX treatment led to autophagic cell death, including in apoptosis-resistant cells.

Conclusions:

  • Acid-labile Me-PRX induces ER stress-mediated autophagic cell death.
  • Me-PRX demonstrates potential as a therapeutic candidate for inducing cell death in apoptosis-resistant malignant tumors.
Keywords:
Autophagic cell deathAutophagyER stressMethylated β-cyclodextrinPolyrotaxane

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