Macrocyclic diterpenes resensitizing multidrug resistant phenotypes.

Abstract

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.

• Authors: Mariana A Reis, Angela Paterna, Ricardo J Ferreira, Hermann Lage, Maria-José U Ferreira
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 14 Pg. 3696-702 (Jul 15 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 24864039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Diterpenes
• Macrocyclic Compounds

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Cell Proliferation (drug effects)
• Diterpenes (chemistry, isolation & purification, 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, isolation & purification, pharmacology)
• Mice
• Molecular Conformation
• Phenotype
• Structure-Activity Relationship
• Tumor Cells, Cultured