Microcystin LR Shows Cytotoxic Activity Against Pancreatic Cancer Cells Expressing the Membrane OATP1B1 and OATP1B3 Transporters

Valentinos Kounnis; Georgios Chondrogiannis; Michalis D Mantzaris; Andreas G Tzakos; Demosthenes Fokas; Nikolaos A Papanikolaou; Vasiliki Galani; Ioannis Sainis; Evangelos Briasoulis

Microcystin LR Shows Cytotoxic Activity Against Pancreatic Cancer Cells Expressing the Membrane OATP1B1 and OATP1B3 Transporters

Anticancer Res. 2015 Nov;35(11):5857-65.

Authors

Valentinos Kounnis¹, Georgios Chondrogiannis², Michalis D Mantzaris³, Andreas G Tzakos⁴, Demosthenes Fokas⁵, Nikolaos A Papanikolaou⁶, Vasiliki Galani², Ioannis Sainis⁷, Evangelos Briasoulis⁸

Affiliations

¹ Molecular Oncology Laboratories, Oxford University, Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, U.K. Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece valentinos.kounnis@oncology.ox.ac.uk.
² Department of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Ioannina, Greece.
³ Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece.
⁴ Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece Department of Chemistry, University of Ioannina, Ioannina, Greece.
⁵ Department of Materials Science and Engineering, University of Ioannina, Ioannina, Greece.
⁶ Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁷ Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece.
⁸ Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece Medical School, University of Ioannina, Ioannina, Greece.

PMID: 26504008

Abstract

Microcystin-LR (MC-LR) is a cyanobacterial cyclopeptide, known for its unique ability to cause acute liver injury. Its cellular uptake is facilitated by specific transmembrane organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and 1B3. The objective of the present study was to investigate the expression of OATPs 1A2, 1B1 and 1B3 in pancreatic cancer cell lines BxPC-3 and MIA PACA-2 and assess their role in MC-LR-mediated cytotoxicity by using the novel xCELLigence system and flow cytometry. OATP1B1 and 1B3 were found to be expressed in both cell lines at both the mRNA and protein levels. The cytotoxic effects of MC-LR were proportionally related to the expression of these transporters. Moreover the cytotoxic potency of MC-LR was found superior to gemcitabine. Based on the expression of the organic anion transporting polypeptides 1B1 and 1B3 in pancreatic carcinoma tissue and cell lines and the potent cytotoxicity induced by MC-LR in vitro, we propose that this molecule could be held as structural basis for the development of novel targeted-compounds against pancreatic cancer.

Keywords: OATPs; Organic anion-transporting polypeptides; cancer treatment; drug development; microcystin-LR; pancreatic cancer; targeted-therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Apoptosis / drug effects*
Biological Transport
Blotting, Western
Cell Proliferation / drug effects
Enzyme Inhibitors / pharmacology*
Flow Cytometry
Humans
Immunoenzyme Techniques
Liver-Specific Organic Anion Transporter 1
Marine Toxins
Microcystins / pharmacology*
Molecular Docking Simulation
Molecular Sequence Data
Organic Anion Transporters / chemistry
Organic Anion Transporters / genetics
Organic Anion Transporters / metabolism*
Organic Anion Transporters, Sodium-Independent / chemistry
Organic Anion Transporters, Sodium-Independent / genetics
Organic Anion Transporters, Sodium-Independent / metabolism*
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
Phosphoprotein Phosphatases / antagonists & inhibitors
Protein Conformation
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Sequence Homology, Amino Acid
Solute Carrier Organic Anion Transporter Family Member 1B3
Tumor Cells, Cultured

Substances

Enzyme Inhibitors
Liver-Specific Organic Anion Transporter 1
Marine Toxins
Microcystins
Organic Anion Transporters
Organic Anion Transporters, Sodium-Independent
RNA, Messenger
SLCO1B1 protein, human
SLCO1B3 protein, human
Solute Carrier Organic Anion Transporter Family Member 1B3
Phosphoprotein Phosphatases
cyanoginosin LR