Vatalanib sensitizes ABCB1 and ABCG2-overexpressing multidrug resistant colon cancer cells to chemotherapy under hypoxia

Biochem Pharmacol. 2015 Sep 1;97(1):27-37. doi: 10.1016/j.bcp.2015.06.034. Epub 2015 Jul 20.

Abstract

Cancer microenvironment is characterized by significantly lower oxygen concentration. This hypoxic condition is known to reduce drug responsiveness to cancer chemotherapy via multiple mechanisms, among which the upregulation of the ATP-binding cassette (ABC) efflux transporters confers resistance to a wide variety of structurally unrelated anticancer drugs. Vatalanib (PTK787/ZK22584) is a multitargeted tyrosine kinase inhibitor for all isoforms of VEGFR, PDGFR and c-Kit, which exhibit potent anticancer activity in vitro and in vivo. We investigated the potentiation effect of vatalanib on the anticancer activity of conventional cytotoxic drugs in colon cancer cell lines under both normoxic and hypoxic conditions. Mechanistically, vatalanib was found to inhibit ABCG2 and ABCB1 efflux activity, presumably by acting as a competitive inhibitor and interfering with their ATPase activity. Under hypoxic growth condition, ABCG2 and ABCB1-overexpressing cells sorted out by FACS technique as side population (SP) were found to be significantly more responsive to SN-38 (ABCG2 and ABCB1 substrate anticancer drug) in the presence of vatalanib. The anchorage independent soft agar colony formation capacity of the SP cells was remarkably reduced upon treatment with a combination of SN-38 and vatalanib, compared to SN-38 alone. However, vatalanib, at concentrations that produced the circumvention of the transporters-mediated resistance, did not appreciably alter ABCG2/ABCB1 mRNA or protein expression levels or the phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2). Our study thus advocates the further investigation of vatalanib for use in combination chemotherapy to eradicate drug-resistant cancer cells under hypoxia.

Keywords: Cancer stem-like cells; Chemosensitization; Doxorubicin hydrochloride (PubChem CID: 443939); Fumitremorgin C (PubChem CID: 403923); Hypoxia; Multidrug resistance transporters; Paclitaxel (PubChem CID: 36314); Pheophorbide A (PubChem CID: 5323510); Rhodamine 123 (PubChem CID: 65217); SN-38 (PubChem CID: 104842); Tariquidar (PubChem CID: 148201); Vatalanib; Vatalanib (PubChem CID: 151194).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Angiogenesis Inhibitors / pharmacology*
  • Antineoplastic Agents, Phytogenic / agonists
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Camptothecin / agonists
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • HEK293 Cells
  • Humans
  • Irinotecan
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phthalazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyridines / pharmacology
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Phytogenic
  • Isoenzymes
  • Neoplasm Proteins
  • Phthalazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Recombinant Proteins
  • vatalanib
  • Irinotecan
  • Proto-Oncogene Proteins c-kit
  • Receptors, Platelet-Derived Growth Factor
  • Receptors, Vascular Endothelial Growth Factor
  • Camptothecin