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KMID : 0043320190420090815
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Archives of Pharmacal Research
2019 Volume.42 No. 9 p.815 ~ p.823
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Induction of p53-mediated senescence is essential for the eventual anticancer therapeutic effect of RH1
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Jung Joo-Hee
Song Do-Young
Hwang Jung-Jin
Park Heon-Joo
Lee Jung-Shin
Song Si-Yeol
Jeong Seong-Yun
Choi Eun-Kyung
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Abstract
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RH1 (2, 5-diaziridinyl-3-(hydroxymethy)-6-methyl-1, 4-benzoquinone) is a bioreductive anticancer drug. The mechanism underlying its therapeutic properties has not yet been elucidated. In this study, we aimed to determine whether RH1 exerts its anticancer effect via p53-mediated apoptosis and senescence in vitro and in vivo. RH1 displayed dose-dependent biphasic effects in vitro, i.e., it induced apoptosis at higher dose and senescence at lower dose accompanied by marked activation of p53. Thus, RH1 primarily induced cell death by apoptosis. The cytotoxicity of RH1 was inhibited in A549 cells treated with the p53-inhibitor pifithrin-α or transfected p53 siRNA and in human colon cancer HCT116 isogenic (p53?/?) cells. At sub-lethal doses of RH1, the cells survived and underwent senescence. The senescent cells showed flattened and enlarged morphology, and exhibited blue color in senescence-associated β-galactosidase staining. These changes were found to be related to p53. RH1-induced senescence decreased in A549-E6 cells (suppressed p53 level) and HCT 116 p53?/? cells. The growth of A549 xenograft tumors in nude mice was significantly delayed by intraperitoneal injection of RH1, and senescent cells were observed in these xenograft tumors. These results suggest that the in vivo anticancer therapeutic effect of RH1 is mediated by senescence via p53 activation.
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KEYWORD
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RH1, Anticancer, Senescence, Apoptosis, p53, Tumor growth delay
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