Proapoptotic effect on normal and tumor intestinal cells of cytostatic drugs with enterohepatic organotropism.
The proapoptotic effect of cisplatin bile acid derivatives Bamet-R2 [cis-diamminechloro-cholylglycinate-platinum(II)] and Bamet-UD2 [cis-diammine-bisursodeoxycholate-platinum(II)], developed to treat liver and intestinal tumors, was investigated in vitro using human enterohepatic cells HepG2 (hepatoblastoma), LS 174T (colon adenocarcinoma), and its cisplatin-resistant subline LS 174T/R. Uptake by wild-type tumor cells was higher for Bamets than for cisplatin. In LS 174T/R cells, copper transporter-1 was down-regulated and multidrug resistance-associated protein-2 was up-regulated. Consequently, uptake and efflux of cisplatin, but not those of Bamets, were reduced and increased, respectively. The degree of necrosis (lactate dehydrogenase release) induced by these three drugs was small and similar in all cell types. In contrast, proapoptotic effect (caspase-3 activity and DNA fragmentation) was Bamet-UD2 > cisplatin > Bamet-R2 in HepG2 and LS 174T cells, but Bamet-UD2 > Bamet-R2 >> cisplatin in LS 174T/R cells. This effect was consistent with the ability of these compounds to form DNA-adducts (DNA-platination, changes in the DNA melting temperature, and MspI-induced restriction sequence cleavage). Oral administration of Bamet-UD2 to mice induced mild apoptosis in the small intestine (ileum > duodenum), which was not severe enough to modify its structure or function as determined by water absorption and glycocholic acid uptake by in situ perfused ileum. These results indicate that Bamet-UD2 overcomes the resistance to cisplatin when this is due in part to enhanced ability of intestinal tumors to reduce intracellular cisplatin contents. Moreover, its strong proapoptotic versus its weak pronecrotic effect together with its mild effect on normal tissues, including intestinal mucosa, may account for the high antitumor activity of Bamet-UD2 together with its very low toxicity.
Monte
Maria J
MJ
Department of Physiology and Pharmacology, University of Salamanca, Spain.
Ballestero
Maria R
MR
Briz
Oscar
O
Perez
Maria J
MJ
Marin
Jose J G
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D051379:Mice; D009336:Necrosis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; C416424:Bamet-UD2; D018736:DNA Adducts; D009944:Organoplatinum Compounds; C408382:diamminebis(ursodeoxycholate(O,O'))platinum(II); D014580:Ursodeoxycholic Acid