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.