Macrocyclic diterpenes resensitizing multidrug resistant phenotypes

Bioorg Med Chem. 2014 Jul 15;22(14):3696-702. doi: 10.1016/j.bmc.2014.05.006. Epub 2014 May 13.


Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2-11) were evaluated for their activity on three different Human cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2-11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity.

Keywords: Antiproliferative activity; Collateral sensitivity; Macrocyclic diterpenes; Multidrug resistance in cancer; P-glycoprotein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / isolation & purification
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Proliferation / drug effects
  • Diterpenes / chemistry
  • Diterpenes / isolation & purification
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • Euphorbia / chemistry
  • HT29 Cells
  • Humans
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / isolation & purification
  • Macrocyclic Compounds / pharmacology*
  • Mice
  • Molecular Conformation
  • Phenotype
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Phytogenic
  • Diterpenes
  • Macrocyclic Compounds