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Macrocyclic diterpenes resensitizing multidrug resistant phenotypes.

Mariana A Reis1, Angela Paterna1, Ricardo J Ferreira1

  • 1Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

Bioorganic & Medicinal Chemistry
|May 28, 2014
PubMed
Summary
This summary is machine-generated.

Macrocyclic diterpenes, including jolkinol D, show collateral sensitivity, effectively targeting multidrug-resistant cancer cells. This strategy highlights promising compounds like jolkinoate L for overcoming cancer drug resistance.

Keywords:
Antiproliferative activityCollateral sensitivityMacrocyclic diterpenesMultidrug resistance in cancerP-glycoprotein

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Area of Science:

  • Natural Products Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancer significantly limits therapeutic efficacy.
  • Collateral sensitivity offers a strategy to identify compounds effective against resistant cancer cells.
  • Macrocyclic diterpenes are a class of natural products with potential anticancer activities.

Purpose of the Study:

  • To evaluate the collateral sensitivity effect of eleven macrocyclic diterpenes, including jolkinol D and its derivatives, against human cancer cell lines.
  • To identify compounds that can overcome resistance mechanisms like P-glycoprotein overexpression and altered topoisomerase II expression.
  • To explore the relationship between P-glycoprotein modulation and antiproliferative activity.

Main Methods:

  • In vitro evaluation of antiproliferative activity of eleven macrocyclic diterpenes against gastric, pancreatic, and colon cancer cell lines, including drug-resistant variants.
  • Assessment of collateral sensitivity effect towards mitoxantrone- and daunorubicin-resistant cell lines.
  • Regression analysis correlating antiproliferative activity with previously determined P-glycoprotein modulatory effects.

Main Results:

  • Jolkinol D and several derivatives exhibited significant collateral sensitivity in P-glycoprotein-overexpressing (EPG85-257RN) and topoisomerase II-altered (HT-29RD) resistant cancer cells.
  • Jolkinoate L (a benzoyl derivative) demonstrated broad targeting ability and high antiproliferative activity across different cellular contexts.
  • A strong correlation was found between high P-glycoprotein modulation and potent cytotoxicity, validating the collateral sensitivity strategy.

Conclusions:

  • Macrocyclic diterpenes, particularly jolkinol D derivatives, are effective in overcoming specific multidrug resistance mechanisms in cancer.
  • Jolkinoate L shows promise as a potent anticancer agent with broad applicability.
  • The study validates collateral sensitivity as a viable strategy for discovering novel anticancer compounds targeting MDR.