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

doi:10.1074/jbc.m109.070466

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 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.

Highlights

The p53 tumor suppressor is essential for maintaining genomic stability in mammals
Given that decreased sensitivity to anti-cancer agents in p53deficient human cancer cells is the major limitation to cancer therapeutics, our search was focused on identifying an antiproliferative compound selective to cells without wild type p53 function (Fig. 1B)
Because cells with defective p53 are relatively resistant to apoptosis and, to chemotherapeutic agents, it is appropriate to seek out cytotoxic agents that induce apoptosis in p53-defective cells

Summary

Introduction

The p53 tumor suppressor is essential for maintaining genomic stability in mammals. When cells are subjected to stress signals such as hypoxia, radiation, or chemotherapeutic drugs, p53 is activated, and its ubiquitin-dependent degradation is blocked leading to an accumulation of active p53 transcription factor [1]. A new isoquinolinium derivative, cadein1 (cancer-selective death inducer 1), was identified in the screen, which induces apoptosis most effectively in p53-defective carcinoma cells with functional MMR. Cadein1 Efficiently Induces Apoptosis in p53-defective Cancer Cells via the Caspase Pathway and Transient G2/M Delay— To determine the optimal conditions for cadein1 treatment, we first performed MTT assays to assess the effective concentration range for inhibition of cell growth in HeLa, IMR90, and WI-38 cells.

Results

Conclusion