Acquired resistance to miriplatin in rat hepatoma AH109A/MP10 is associated with increased Bcl-2 expression, leading to defects in inducing apoptosis.
Miriplatin, a novel lipophilic platinum complex approved to treat hepatocellular carcinoma, is administered into the hepatic artery after suspension in an oily contrast medium. Little is known concerning the mechanism of acquired resistance to miriplatin. In this study, we established and characterized a rat hepatoma cell subline, AH109A/MP10, which was about 10-fold more resistant to miriplatin than the parental cell line, AH109A. The established miriplatin-resistant cells showed clear cross-resistance to platinum complexes containing diaminocyclohexane as a carrier ligand, such as oxaliplatin and dichloro[(1R,2R)-1,2-cyclohexanediamine-N,N']platinum (DPC), while three human cancer cell lines selected for resistance to cisplatin (A2780cis, NCI-H69/CPR, MOR/CPR) did not show cross-resistance to miriplatin. There was no apparent difference in either intracellular platinum accumulation or platinum-DNA adducts in formation between resistant and parental cells after treatment with miriplatin or cisplatin, consisted with the unchanged expression of proteins involved in DNA repair, such as excision repair cross-complementing 1 (ERCC1) and mutL homolog 1 (MLH1). The increased expression of Bcl-2 was observed in AH109A/MP10 cells, in which apoptosis induced by miriplatin, but not cisplatin, was reduced. In addition, Bcl-2 inhibitor YC137 partially reversed the resistance of AH109A/MP10 cells to miriplatin. These findings suggested that the acquired resistance to miriplatin in AH109A/MP10 cells was associated in part with increased Bcl-2 expression, leading to defects in inducing apoptosis.
Hanada
Mitsuharu
M
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Konohana-ku, Osaka 554-0022, Japan. mitsuharu-hanada@ds-pharma.co.jp
Takasu
Hideo
H
Kitaura
Makoto
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016461:Chemoembolization, Therapeutic / Q000379:methods; D002945:Cisplatin / Q000494:pharmacology; D045643:DNA Repair Enzymes / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000628:therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; C406530:miriplatin; D045643:DNA Repair Enzymes; D002945:Cisplatin