A new isoquinolinium derivative, cadein1, preferentially induces apoptosis in p53-defective cancer cells with functional mismatch repair via a p38-dependent pathway

Eun Ryoung Jang, Minsook Ryu, Jeong Eun Park, Jung Ho Kim, Jong Soo Lee, Kiwon Song

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9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2986-2995
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number5
DOIs
Publication statusPublished - 2010 Jan 29

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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