A new isoquinolinium derivative, Cadein1, preferentially induces apoptosis in p53-defective cancer cells with functional mismatch repair via a p38-dependent pathway.
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 G(2)/M delay and caspase-dependent apoptosis in various carcinoma cells with non- functional p53. The ability of cadein1 to induce apoptosis in p53-defective colon cancer cells was tightly linked to the presence of a functional DNA mismatch 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 the MMR status. Consistently, when the function of MMR was blocked with short hairpin RNA in SW620 (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.
Jang
Eun Ryoung
ER
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Ryu
Minsook
M
Park
Jeong Eun
JE
Kim
Jung-Ho
JH
Lee
Jong-Soo
JS
Song
Kiwon
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D020137:Base Pair Mismatch; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004260:DNA Repair / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016158:Genes, p53; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008956:Models, Chemical; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D007546:Isoquinolines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C547272:cadein1 compound; D048051:p38 Mitogen-Activated Protein Kinases