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A new mixed-backbone oligonucleotide against glucosylceramide synthase sensitizes multidrug-resistant tumors to

Gauri A Patwardhan1, Qian-Jin Zhang, Dongmei Yin

  • 1Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, Louisiana, United States of America.

Plos One
|September 11, 2009
PubMed

Insights

Glucosylceramide synthase (GCS) hinders chemotherapy effectiveness in resistant cancers. A novel mixed-backbone oligonucleotide (MBO-asGCS) targeting GCS resensitized tumors to doxorubicin, showing potential as an anticancer agent.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Enhanced ceramide glycosylation by glucosylceramide synthase (GCS) contributes to resistance against antineoplastic agents like doxorubicin in cancer cells.
  • Targeting GCS is a potential strategy to overcome multidrug resistance in cancer therapy.

Purpose of the Study:

  • To investigate the role of GCS in tumor chemoresistance.
  • To develop and evaluate a novel mixed-backbone oligonucleotide (MBO-asGCS) designed to silence the human GCS gene for enhancing cancer treatment efficacy.

Main Methods:

  • Generation of a mixed-backbone oligonucleotide (MBO-asGCS) to specifically silence the GCS gene.
  • Assessment of MBO-asGCS uptake and its effect on GCS expression and activity in drug-sensitive and drug-resistant cancer cells.
  • Evaluation of MBO-asGCS in combination with doxorubicin in both in vitro cell lines and in vivo tumor models.

Main Results:

  • MBO-asGCS was efficiently internalized by cancer cells and selectively suppressed GCS overexpression.
  • Significant sensitization to doxorubicin was observed in drug-resistant cell lines (83-fold in NCI/ADR-RES, 43-fold in EMT6/AR1).
  • In vivo, MBO-asGCS treatment inhibited multidrug-resistant tumor growth by 37% and enhanced doxorubicin efficacy over 2-fold, linked to reduced GCS activity and increased apoptosis.

Conclusions:

  • Glucosylceramide synthase (GCS) is a viable therapeutic target for overcoming cancer drug resistance.
  • MBO-asGCS effectively resensitizes multidrug-resistant tumors to chemotherapy with minimal toxicity to vital organs.
  • MBO-asGCS demonstrates potential as a novel therapeutic agent for treating chemoresistant cancers.

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