The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy

J Enzyme Inhib Med Chem. 2019 Dec;34(1):117-123. doi: 10.1080/14756366.2018.1532419.

Abstract

Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement conventional chemotherapy, carbonic anhydrase IX (CAIX) inhibitors appear as one of the most suitable, as markers of hypoxic and acidic cancer cells which do not respond to chemo- and radiotherapy. We performed preclinical in vitro assays to evaluate whether the SLC-0111 CAIX inhibitor co-operates and potentiates the cytotoxic effects of conventional chemotherapeutic drugs in A375-M6 melanoma cells, MCF7 breast cancer cells, and HCT116 colorectal cancer cells. Here, we demonstrate that the SLC-0111 CAIX inhibitor potentiates cytotoxicity of Dacarbazine and Temozolomide currently used for advanced melanoma treatment. SLC-0111 also increases breast cancer cell response to Doxorubicin and enhances 5-Fluorouracil cytostatic activity on colon cancer cells. These findings disclose the possibility to extend the use of CAIX inhibitors in the combination therapy of various cancer histotypes.

Keywords: CAIX inhibitor; Chemotherapy; SLC-0111; combined therapy; drug resistance.

MeSH terms

  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / chemistry
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Carbonic Anhydrase IX / antagonists & inhibitors*
  • Carbonic Anhydrase IX / genetics
  • Carbonic Anhydrase IX / metabolism
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / chemistry
  • Dacarbazine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Fluorouracil / chemistry
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Molecular Structure
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Temozolomide
  • Tumor Cells, Cultured

Substances

  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Phenylurea Compounds
  • RNA, Messenger
  • SLC-0111
  • Sulfonamides
  • Dacarbazine
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Fluorouracil
  • Temozolomide

Grants and funding

This study was financially supported by Istituto Toscano Tumori (ITT) (Decreto Dirigenziale Regione Toscana n. 5254 of 04/12/2013 to LC), Ente Cassa di Risparmio di Firenze (to LC), Associazione Italiana per la Ricerca sul Cancro (AIRC) (fellowship to EA) and Università degli Studi di Firenze.