Mononuclear platinum(II) complex with 2-phenylpyridine ligands showing high cytotoxicity against mouse sarcoma 180 cells acquiring high cisplatin resistance.
Mouse sarcoma 180 cell with a 25-fold higher cisplatin (CDDP) resistance, termed S-180cisR, is newly established. S-180cisR cells grow quite slowly in the presence of CDDP with high concentration. This may show that S-180cisR cells modulate the cell cycle to acquire CDDP resistance. P-Glycoprotein is selectively expressed on the surface of S-180cisR, which is not on CDDP-sensitive S-180 parent cells. In an experiment using an inhibitor (verapamil) of P-glycoprotein, cytotoxicity of CDDP against S-180cisR is significantly increased (viz., IC(50) value is decreased) and accumulation of CDDP in S-180cisR cells is also increased. These results indicate that enhanced pumping-out of CDDP by P-glycoprotein should be one of the reasons for the CDDP resistance of S-180cisR. A platinum(II) complex with a cyclometalated 2-phenylpyridine ligand and a nonchelated one (complex 5) is synthesized, and its structure is determined by X-ray structural analysis. Complex 5 has a cyctotoxicity against S-180cisR higher than that of CDDP and its derivatives with 2- or 3-substituted pyridine ligands (complexes 2-4, 6, 7). Complex 5 is incorporated in S-180cisR to an enormously greater extent than CDDP; that is, the ratio of accumulated platinum amount after 3 h is 61.9. In S-180 parent cells, on the other hand, the ratio remains 8.1. This high accumulation of complex 5 into S-180cisR must account for the higher activity of complex 5 against S-180cisR compared to CDDP.
Okada
T
T
Institute of Molecular and Cell Biology, Tsukuba Center, National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
El-Mehasseb
I M
IM
Kodaka
M
M
Tomohiro
T
T
Okamoto
K
K
Okuno
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D012509:Sarcoma; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011725:Pyridines; C443686:chloro(2-phenylpyridine)(2-C6H4C5H4N)platinum(II); C058324:2-phenylpyridine; D014700:Verapamil; D002945:Cisplatin