Microparticle-associated nucleic acids mediate trait dominance in cancer.

Drug resistance is a major cause of cancer treatment failure, with multidrug resistance (MDR) being the most serious, whereby cancer cells display cross-resistance to structurally and functionally unrelated drugs. MDR is caused by overexpression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). These transporters act to maintain sublethal intracellular drug concentrations within the cancer cell, making the population treatment unresponsive. Recently, we discovered a novel nongenetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells. MPs isolated from MDR leukemia and breast cancer cells were cocultured with their drug-sensitive counterparts. P-gp transfer was assessed by direct immunolabeling, and acquired transcripts and regulatory microRNAs by quantitative real-time PCR. We show that MDR MPs incorporate nucleic acids; MPs change recipient cells' transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells' ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and "retemplating" the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology.

Dietary nucleotide supplements in infant formula modify the expression of P-glycoprotein in the intestinal epithelium in vitro.

The effect of dietary nucleotides at concentrations found in supplemented infant formula on P-glycoprotein (P-gp) expression in colon cells was examined. We report that P-gp expression in colon cells was significantly decreased in a time- and concentration-dependent manner. When colon cells were co-cultured with lymphocytes, so as to mimic the involvement of gut-associated lymphoid tissue in normal gut pathophysiology, we observed a reversal of this effect with a demonstrated increase in P-gp expression. These findings have important implications on effects of nucleotide exposure on increasing drug bioavailability, reducing the capacity for xenobiotic efflux, and increasing the risk of inflammatory bowel disease in susceptible infants. Future studies are directed at defining both the mechanisms underlying these findings and effects of dietary nucleotide supplementation in vivo.