Apoptosis induction and inhibition of H-ras overexpression by novel trans-[PtCl2(isopropylamine)(amine')] complexes.
Hitherto, it has been generally accepted as a paradigm of the biochemical pharmacology of platinum antitumor drugs that a cis configuration of the leaving groups is necessary for antitumor activity of platinum compounds. However, it has been recently observed that certain trans-platinum complexes have both in vitro and in vivo antitumor activity. We previously reported the synthesis, characterization and cytotoxic activity against ras-transformed cells of several trans-[PtCl2LL'] complexes where L and L' are asymmetric aliphatic amines (L = dimethylamine and butylamine, L' = isopropylamine). The results reported in this paper show that the compounds trans-[PtCl2(isopropylamine)(dimethylamine)] and trans-[PtCl2(isopropylamine)(butylamine)] kill Pam 212-ras cisplatin resistant cells through apoptosis induction. Moreover, Western blot data show that both compounds inhibit overexpression of H-ras oncogene in Pam 212-ras cells. Altogether, these data indicate that, in contrast with cis-DDP, the apoptotic activity of these novel trans-Pt(II) compounds in ras-transformed cells is associated with their ability to abolish ras-overexpression.
Pérez
J M
JM
Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Spain.
Montero
E I
EI
González
A M
AM
Alvarez-Valdés
A
A
Alonso
C
C
Navarro-Ranninger
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002461:Cell Line, Transformed / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects*; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000187:drug effects / Q000235:genetics; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C122085:dichloro(butylamine)(isopropylamine)platinum(II); C122083:dichloro(isopropylamine)(dimethylamine)platinum(II); D015689:Oncogene Protein p21(ras); D002945:Cisplatin