Overexpression of BP1, a homeobox gene, is associated with resistance to all-trans retinoic acid in acute promyelocytic leukemia cells.

BP1, a homeobox gene, is overexpressed in the bone marrow of 63% of acute myeloid leukemia patients. In this study, we compared the growth-inhibitory and cyto-differentiating activities of all-trans retinoic acid (ATRA) in NB4 (ATRA-responsive) and R4 (ATRA-resistant) acute promyelocytic leukemia (APL) cells relative to BP1 levels. Expression of two oncogenes, bcl-2 and c-myc, was also assessed. NB4 and R4 cells express BP1, bcl-2, and c-myc; the expression of all three genes was repressed after ATRA treatment of NB4 cells but not R4 cells. To determine whether BP1 overexpression affects sensitivity to ATRA, NB4 cells were transfected with a BP1-expressing plasmid and treated with ATRA. In cells overexpressing BP1: (1) proliferation was no longer inhibited; (2) differentiation was reduced two- to threefold; (3) c-myc was no longer repressed. These and other data suggest that BP1 may regulate bcl-2 and c-myc expression. Clinically, BP1 levels were elevated in all pretreatment APL patients tested, while BP1 expression was decreased in 91% of patients after combined ATRA and chemotherapy treatment. Two patients underwent disease relapse during follow-up; one patient exhibited a 42-fold increase in BP1 expression, while the other showed no change. This suggests that BP1 may be part of a pathway involved in resistance to therapy. Taken together, our data suggest that BP1 is a potential therapeutic target in APL.

Thioredoxin reductase as a novel molecular target for cancer therapy.

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential targets for therapeutic intervention. Redox-sensitive signaling factors also regulate multiple cellular processes including proliferation, cell cycle, and pro-survival signaling cascades, suggesting their potential as molecular targets for anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular markers. We hypothesized that thioredoxin reductase-1 (TR), a component of several redox-regulated pathways, may represent a potential molecular target candidate in response to agents that induce oxidative stress. There have been numerous biological studies over the last decade investigating the cell biological, biochemical, and genetic properties of TR both in culture and in in vivo models. In addition, using a series of permanent cell lines that express either a wild-type TR or a dominant mutant TR gene or a chemical agent that inhibits TR we demonstrated that TR meets most criteria that would identify a molecular target. Based on these results we believe TR is a potential molecular target and discuss potential clinical possibilities.

The epigenome as a molecular marker and target.

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential molecular markers, targets, and molecular profiles that should eventually expand and improve therapeutic intervention. It now appears clear that methylation plays a central role in transformation, both in vitro and in vivo. However, the exact targets and mechanism(s) are not yet fully understood. This is partly due to the significant number of genes altered by changes in intracellular methyltransferase activity and the chemical agents used to modulate gene expression. The complex nature of methylation's role in regulating gene expression suggests that in addition to investigating individual genes, researchers should develop more comprehensive methods to examine gene expression patterns and their predictive value as this will likely be necessary in the future. If methylation plays a role in transformation, then it seems logical that genes regulating intracellular methylation status may be used as molecular markers to profile tumors by any new methods currently being developed. Perhaps more noteworthy is that DNMT genes may be found to be novel molecular targets for new factor-specific anticancer agents. This idea will be addressed.

p38 Mitogen-activated protein kinase inhibitor protects the epidermis against the acute damaging effects of ultraviolet irradiation by blocking apoptosis and inflammatory responses.

The primary function of the epidermis is to provide a protective barrier against numerous environmental insults, including ultraviolet radiation (UVR). UVR, particularly in the UVB spectrum, is a potent carcinogen known to damage DNA directly or through the generation of free radicals. Although in the long term, protective measures such as apoptosis and inflammation may prove beneficial in safeguarding the epidermis against the propagation of potentially tumorigenic cells, after high-dose UV irradiation these biologic events may be acutely detrimental to the architectural and functional integrity of the tissue owing to rampant cell death and inflammatory responses, which can culminate in epidermal erosion and consequently loss of barrier functions. The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated by UVR and herein we identify p38 MAPK as a key modulator of these physiologic events. Mice treated with the p38 MAPK inhibitor SB202190 are protected against several detrimental effects of acute UV irradiation, namely, sunburn cell/apoptosis, inflammation, and a hyperproliferation response. Based on our results, selectively blocking p38 activation with the SB202190 inhibitor could prove beneficial in treating victims from severe sunburn or exposure to other chemical agents known to trigger the p38 pathway.