Cytotoxic activity of lutropin-gelonin conjugate in mouse Leydig tumor cells: potentiation of the hormonotoxin activity by different drugs.
A hormonotoxin preparation composed of gelonin, a basic protein of 30,000 Da isolated from the plant Gelonium multiflorum and the luteinizing hormone (LH, lutropin) isolated from the sheep pituitary has been studied for its cytotoxic action on mouse testicular Leydig tumor cells (MA-10 cells). Gelonin modified with 2-iminothiolane and conjugated with hormone modified by N-succinimidyl-3-2-pyridyl dithiopropionate was able to inhibit protein synthesis in Leydig tumor cells. An enhancement of the cytotoxicity of the hormonotoxin was obtained in the presence of drugs like quinacrine, chloroquine, verapamil and monensin. We report that the cytotoxicity of hormonotoxin was enhanced 10-15 times with quinacrine (7.6 microM), chloroquine (29 microM), verapamil (40 microM) and monensin (0.29 microM). While quinacrine, chloroquine and verapamil were not cytotoxic to MA-10 cells for up to 48 h, monensin alone reduced protein synthesis significantly in 48 h. All the drugs studied here inhibited steroidogenic action of the native hormone even at concentrations which were not detrimental to protein synthesis. On the basis of the above studies, we suggest that it may be feasible to develop combination strategies to destroy gonadal cells bearing gonadotropin (LH) receptors. In cells not bearing LH receptors (COS-7 cell line) there was no cytotoxicity either with hormonotoxin alone or in combination with the drugs, suggesting specificity of action.
Marcil
J
J
Reproduction Research Laboratory, Clinical Research Institute of Montreal, Que., Canada.
Ravindranath
N
N
Sairam
M R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D007984:Leydig Cell Tumor / Q000188:drug therapy / Q000473:pathology*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008985:Monensin / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010940:Plant Proteins / Q000494:pharmacology*; D011374:Progesterone / Q000096:biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D011974:Receptors, LH / Q000187:drug effects; D054789:Ribosome Inactivating Proteins, Type 1; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010940:Plant Proteins; D011500:Protein Synthesis Inhibitors; D011974:Receptors, LH; D054789:Ribosome Inactivating Proteins, Type 1; D011374:Progesterone; C025674:GEL protein, Gelonium multiflorum; D002738:Chloroquine; D007986:Luteinizing Hormone; D008985:Monensin; D014700:Verapamil; D011796:Quinacrine