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.