An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities.
We describe the biological activity of some furylbenzo- and naphthoquinones (furylquinones) on hepatocarcinoma cells and healthy rat liver slices. The effects of furylquinones on cancer cells (Transplantable Liver Tumor, TLT) were assessed by measuring cell death (membrane cell lysis); intracellular contents of ATP and GSH and the activity of caspase-3 were used to determine the type of cell death. Most of the furylquinones tested (at a concentration of 25 μg/ml) induced caspase-independent cell death but compound 4 had no cytotoxic effects. The levels of both ATP and GSH were severely affected by quinones 1, 2 and 5, while no effect was observed with compound 4. These cytotoxic properties of quinones are associated with physico-chemical properties as shown by the LUMO energies and lipophilicity. Interestingly, no cytotoxic effects of furylquinones were detected when the in vitro model of precision-cut liver slices (PCLS) was used. Indeed, although CYP2E1 activity was slightly affected, ATP and GSH levels as well as protein synthesis were not modified by furylquinones. Paracetamol, a well-known hepatotoxicant, reduced these parameters by more than 80% compared to control conditions. Taking into account the considerable incidence of adverse-effects induced by most current anticancer drugs, the selective cytotoxicity shown by compounds 1, 2 and 5, in particular that of 1, represents a safety factor that encourages the further development of these quinones as new drugs in cancer therapy.
Departamento de Ciencias Químicas y Farmacéuticas, Universidad Arturo Prat, Iquique, Chile, Avenida Arturo Prat 2120, Casilla 121, Iquique, Chile.
Julio
J
Benites
Jaime A
JA
Valderrama
Henryk
H
Taper
Pedro
P
Buc Calderon
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D014176:Protein Biosynthesis / Q000187:drug effects; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012984:Software
D000970:Antineoplastic Agents; D011809:Quinones; D000255:Adenosine Triphosphate; D019392:Cytochrome P-450 CYP2E1; D053148:Caspase 3; D005978:Glutathione