Lamellarin O, a pyrrole alkaloid from an Australian marine sponge, Ianthella sp., reverses BCRP mediated drug resistance in cancer cells

Mar Drugs. 2014 Jun 27;12(7):3818-37. doi: 10.3390/md12073818.

Abstract

ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1-12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure-activity relationship analysis inclusive of the natural products 1-12 and the synthetic analogues 13-19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / physiology
  • Animals
  • Australia
  • Coumarins / pharmacology*
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm / drug effects*
  • Fluoresceins / metabolism
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Isoquinolines / pharmacology*
  • Mitoxantrone / metabolism
  • Molecular Docking Simulation
  • Multidrug Resistance-Associated Proteins / physiology
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • Porifera / metabolism*
  • Structure-Activity Relationship

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Coumarins
  • Fluoresceins
  • Heterocyclic Compounds, 4 or More Rings
  • Isoquinolines
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • lamellarin O
  • Doxorubicin
  • Mitoxantrone
  • fluorexon
  • multidrug resistance-associated protein 1