TY - JOUR
T1 - A new isoquinolinium derivative, cadein1, preferentially induces apoptosis in p53-defective cancer cells with functional mismatch repair via a p38-dependent pathway
AU - Jang, Eun Ryoung
AU - Ryu, Minsook
AU - Park, Jeong Eun
AU - Kim, Jung Ho
AU - Lee, Jong Soo
AU - Song, Kiwon
PY - 2010/1/29
Y1 - 2010/1/29
N2 - We screened a protoberberine backbone derivative library for compounds with anti-proliferative effects on p53-defective cancer cells. A compound identified from this small molecule library, cadein1 (cancer-selective death inducer 1), an isoquinolinium derivative, effectively leads to a G2/M delay and caspase-dependent apoptosis in various carcinoma cells with nonfunctional p53. The ability of cadein1 to induce apoptosis in p53-defective colon cancer cells was tightly linked to the presence ofa functionalDNAmismatch repair(MMR)system, which is an important determinant in chemosensitivity. Cadein1 was very effective in MMR+/p53- cells, whereas it was not effective in p53+ cells regardless of theMMRstatus. Consistently, when the function ofMMRwas blocked with short hairpinRNAinSW620 (MMR+/p53 -) cells, cadein1 was no longer effective in inducing apoptosis. Besides, the inhibition of p53 increased the pro-apoptotic effect of cadein1 in HEK293(MMR+/p53+) cells, whereas it did not affect the response to cadein1 in RKO (MMR-/p53+) cells. The apoptotic effects of cadein1 depended on the activation of p38 but not on the activation of Chk2 or other stress-activated kinases in p53-defective cells. Taken together, our results show that cadein1 may have a potential to be an anti-cancer chemotherapeutic agent that is preferentially effective on p53-mutant colon cancer cells with functional MMR.
AB - We screened a protoberberine backbone derivative library for compounds with anti-proliferative effects on p53-defective cancer cells. A compound identified from this small molecule library, cadein1 (cancer-selective death inducer 1), an isoquinolinium derivative, effectively leads to a G2/M delay and caspase-dependent apoptosis in various carcinoma cells with nonfunctional p53. The ability of cadein1 to induce apoptosis in p53-defective colon cancer cells was tightly linked to the presence ofa functionalDNAmismatch repair(MMR)system, which is an important determinant in chemosensitivity. Cadein1 was very effective in MMR+/p53- cells, whereas it was not effective in p53+ cells regardless of theMMRstatus. Consistently, when the function ofMMRwas blocked with short hairpinRNAinSW620 (MMR+/p53 -) cells, cadein1 was no longer effective in inducing apoptosis. Besides, the inhibition of p53 increased the pro-apoptotic effect of cadein1 in HEK293(MMR+/p53+) cells, whereas it did not affect the response to cadein1 in RKO (MMR-/p53+) cells. The apoptotic effects of cadein1 depended on the activation of p38 but not on the activation of Chk2 or other stress-activated kinases in p53-defective cells. Taken together, our results show that cadein1 may have a potential to be an anti-cancer chemotherapeutic agent that is preferentially effective on p53-mutant colon cancer cells with functional MMR.
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U2 - 10.1074/jbc.M109.070466
DO - 10.1074/jbc.M109.070466
M3 - Article
C2 - 19948725
AN - SCOPUS:77449124806
VL - 285
SP - 2986
EP - 2995
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 5
ER -