Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport

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Updated: Jul 16, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

J Sims-Mourtada1, J G Izzo, J Ajani

  • 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Oncogene
|March 14, 2007
PubMed

Insights

Inhibiting the Hedgehog (Hh) pathway enhances chemotherapy effectiveness by reducing multi-drug resistance (MDR) in cancer cells. Hh signaling increases drug efflux via ATP-binding cassette (ABC) transporters, contributing to MDR.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Multi-drug resistance (MDR) is a significant challenge in chemotherapy, often caused by increased drug efflux mediated by ATP-binding cassette (ABC) transporters.
  • The regulation of ABC transporters in cancer and their role in MDR are not fully understood, limiting effective clinical strategies.
  • Constitutive activation of the Hedgehog (Hh) signaling pathway is implicated in the growth and maintenance of various cancers.

Purpose of the Study:

  • To investigate the role of Hedgehog (Hh) signaling in chemoresistance and explore its potential as a therapeutic target.
  • To determine if Hh pathway activation influences the expression and function of ATP-binding cassette (ABC) transporters involved in multi-drug resistance (MDR).

Main Methods:

  • Assessing the impact of Hh signaling inhibition on cancer cell response to various chemotherapies.
  • Investigating the mechanism by which Hh pathway activation induces chemoresistance, focusing on drug efflux and ABC transporter activity.
  • Analyzing the regulation of specific ABC transporters, including MDR1 (ABCB1) and BCRP (ABCG2), by Hh signaling.
  • Utilizing small interfering RNA (siRNA) to knock down MDR1 and BCRP expression and evaluate its effect on Hh-induced chemoresistance.

Main Results:

  • Inhibition of Hh signaling significantly improved cancer cell sensitivity to multiple chemotherapeutic agents.
  • Hedgehog (Hh) pathway activation was found to induce chemoresistance, at least partially, by enhancing drug efflux dependent on ATP-binding cassette (ABC) transporters.
  • Hh signaling was demonstrated to regulate the expression of key ABC transporters, namely multi-drug resistance protein-1 (MDR1, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2).
  • Targeted knockdown of MDR1 and BCRP expression using small interfering RNA (siRNA) partially reversed the chemoresistance induced by Hh pathway activation.

Conclusions:

  • The Hedgehog (Hh) signaling pathway plays a crucial role in mediating chemoresistance in cancer.
  • Hh pathway activation contributes to multi-drug resistance (MDR) by upregulating ATP-binding cassette (ABC) transporters involved in drug efflux.
  • Targeting the Hh pathway presents a promising strategy to overcome MDR and enhance the efficacy of chemotherapy in cancer treatment.

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