Diverse effects of 9-hydroxyellipticine on the chemosensitivity of human pancreatic cancer cells harboring p53 mutations.
Recently, it has been shown that 9-hydroxyellipticine (9-HE), an antitumor alkaloid has a unique property of restoring functional wild-type (wt) p53 activity via inhibition of mutant (mt) p53 protein phosphorylation. In the present study, we investigated the effect of 9-HE on the drug sensitivity of human pancreatic cancer cells. Exposure of cells to 9-HE at a relatively low concentration of 1 microM induced almost no cell death but was sufficient to restore wt p53 activity, as evidenced by an induction of endogenous p21WAF1/CIP1 concomitant with G1 and G2/M arrests in cell-cycle progression. Pretreatment with 1 microM 9-HE markedly enhanced cell killing when combined with cisplatin or mitomycin C. In contrast, 9-HE pretreatment protected cells from killing by 5-fluorouracil, VP-16, or vincristine. These effects of 9-HE were specific for several cell lines containing mt p53 and were not observed in p53-negative or wt p53 expressing cells. Taken together, these findings suggest that 9-HE may exert different effects on the drug sensitivity of pancreatic cancer cells displaying p53 mutations possibly through restoration of wt p53.
Mizumoto
K
K
Department of Surgery and Oncology, Graduate School of Medicine, Kyushu University, Fukuoka, Japan. mizumoto@mailserver.med.kyushu-u.ac.jp
Sato
N
N
Kusumoto
M
M
Niiyama
H
H
Maehara
N
N
Nishio
S
S
Li
Z
Z
Ogawa
T
T
Tanaka
M
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D016903:Drug Monitoring; D004611:Ellipticines / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004611:Ellipticines; D016159:Tumor Suppressor Protein p53; C008009:9-hydroxyellipticine