Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone) and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient, high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy. [Mol Cancer Ther 2006;5(4):952 -61]

Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (Ͻ Ͻ 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. IntroductionDyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome (IBMFS). Patients with DC typically present with progressive bone marrow failure (BMF) and the classic triad of mucocutaneous features, including abnormal pigmentation, dystrophic nail changes, and leukoplakia of the oral mucosa. 1-3 Disease penetrance is highly variable, ranging from hardly detectable, to severe forms causing death in early childhood, as seen in Hoyeraal Hreidarson (HH) syndrome. With the identification of 6 genes that when mutated can cause DC (DKC1, TERC, TERT, NOP10, NHP2, and TINF2) 4-9 and the availability of genetic testing, it has become increasingly evident that the classic mucocutaneous features are only present in a small proportion of patients with DC, suggesting that a diagnosis based on the presence of these manifestations alone is likely to overlook a significant proportion of patients with DC. 10 Screening for pathogenic mutations is expensive, time-consuming, and, in approximately half of patients, inconclusive. Thus, using the methods currently available, mutation screening does not seem to be a suitable screening test for the diagnosis of DC. However, all genes implicated in DC are involved in telomere maintenance, suggesting that dysfunctional and excessively short telomeres are the common denominator in this disease and that short and dysfunctional telomeres play an important role in the pathogenesis of disease in patients with DC.Telomeres are complex DNA-protein structures at the end of chromosomes. 11,12 In most eukaryotes including humans, telomeric DNA is composed of guanine-rich DNA repeat sequences. 13 Telomeres shorten with each cell division. 14 When telomeres become critically short, a DNA damage response is activated, causing cell cycle arrest or cell death. 15 In humans, telomerasebased telomere elongation is the major mechanism that counteracts this process of continuous telomere shortening. 16,17 ...

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