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Epoxylathyrane Derivatives as MDR-Selective Compounds for Disabling Multidrug Resistance in Cancer

Mariana Alves Reis1, Ana M Matos1, Noélia Duarte1

  • 1Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal.

Frontiers in Pharmacology
|May 28, 2020
PubMed
Abstract

Insights

New epoxylathyrane derivatives show collateral sensitivity (CS) effects, enhancing chemotherapy against multidrug resistance (MDR). Compounds 8, 15, and 16 were particularly effective, with compound 8 showing significant MDR-selective antiproliferative activity in gastric cancer cells.

Area of Science:

  • Medicinal Chemistry
  • Cancer Pharmacology
  • Molecular Biology

Background:

  • Multidrug resistance (MDR) significantly hinders cancer chemotherapy efficacy.
  • Collateral sensitivity (CS) offers a promising strategy to overcome MDR.
  • Epoxylathyrane derivatives were synthesized from epoxyboetirane A, targeting P-glycoprotein (P-gp/ABCB1) efflux.

Purpose of the Study:

  • To develop lathyrane-type macrocyclic diterpenes with enhanced MDR-modifying activity.
  • To investigate compounds targeting multiple anti-MDR mechanisms.

Main Methods:

  • Evaluated CS effect of epoxylathyrane derivatives (1-16) against sensitive and resistant human gastric, pancreatic, and colon cancer cell lines.
  • Assessed apoptosis induction by promising compounds (8, 15, 16) using annexin V/PI and active caspase-3 assays.
  • Utilized regression models to establish structure-activity relationships for CS effects.

Main Results:

  • Compounds demonstrated greater efficacy against resistant gastric cell lines, with significant CS in EPG85-257RDB cells.
  • Compounds 8, 15, and 16 exhibited the best overall results, with compound 8 showing a 10-fold increase in activity against resistant gastric cells.
  • Compounds 15 and 16 induced apoptosis via caspase-3 activation, elucidating their CS mechanism.

Conclusions:

  • Lathyrane-type diterpenes are valuable lead compounds for developing novel MDR-modifying agents.
  • The study highlights the potential of targeting MDR through collateral sensitivity mechanisms.
Keywords:
Euphorbiaapoptosiscollateral sensitivitylathyranemacrocyclic diterpenesmultidrug resistanceregression models

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