Effects of PRIMA-1 on wild-type L1210 cells expressing mutant p53 and drug-resistant L1210 cells lacking expression of p53: necrosis vs. apoptosis.

The effects of PRIMA-1 on wild-type (WT) mouse leukemia L1210 cells and drug-resistant L1210 cells (Y8) were studied with respect to the induction of apoptosis and necrosis in these cell lines. The WT L1210 cells express mutant p53 while the Y8 L1210 cells do not express p53 mRNA or protein, but do express WAF1/p21 and Gadd 45 mRNA's and proteins. It was found that, in response to treatment with PRIMA-1, the WT L1210 cells became necrotic with little apoptosis while the Y8 L1210 cells showed a much higher level of apoptosis than necrosis. Flavopiridol in combination with PRIMA-1 caused a synergistic increase in necrosis in the WT L1210 cells while LY 294002 in combination with PRIMA-1 caused a synergistic increase in apoptosis in the Y8 L1210 cells. These studies showed that PRIMA-1 had an effect not only on cells expressing mutant p53, but also on cells that do not express p53, suggesting that PRIMA-1 and PRIMA-1-like molecules have multiple sites of action independent of restoring p53 function and that these can interact with other signaling pathways involving CDK's and PI3 kinases.