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Thalassemia and sickle-cell anemia (SCA) present a major public health problem in countries where the number of carriers and affected individuals is high. As a result of the abnormalities in hemoglobin production, cells of thalassemia and SCA patients exhibit oxidative stress, which ultimately is responsible for the chronic anemia observed. Therefore, identification of compounds exhibiting both antioxidant and hemoglobin-inducing activities is highly needed. Our results demonstrate resveratrol to be such a compound. This was shown both in the human K562 cell line, as well as in erythroid precursors derived from normal donors and β-thalassemia patients. Resveratrol was shown to exhibit antioxidant activity and to stimulate the expression of the γ-globin genes and the accumulation of fetal hemoglobin (HbF). To the best of our knowledge, this is the first report pointing to such a double effect of resveratrol. Since this natural product is already marketed as an antioxidant, future investigations should concentrate on demonstrating its potential to augment HbF production in experimental animal models (e.g., thalassemia and SCA mice) as well as in patients. We believe that the potential of clinical use of resveratrol as an antioxidant and HbF stimulator may offer a simple and inexpensive treatment to patients.

Derivatives of distamycin A modified at the C-terminal amidine moiety and tethered to bis-epoxyethyl moieties at the N-terminal position were tested for their ability to induce erythroid differentiation in the human erythroleukemic cell line K562. None of the compounds without bis-epoxyethyl moiety were active. A comparison of the biological activity of diepoxy compounds containing different non-basic amidine-modified moieties, showed low activity of amidoxime, carbamoyl and N-methyl carbamoyl derivatives as differentiation agents. In contrast, a cyanamidine derivative, compound 3, was able to induce erythroid differentiation of K562 cells. In addition, the cyanamidine derivative 3 was able to induce HbF accumulation following treatment of cultures of erythroid precursor cells isolated from the peripheral blood of normal subjects.

The inhibition of gene transcription mediated by peptide nucleic acids (PNAs) has been described as mainly due to a process that involves strand invasion of target DNA containing homopurine stretches with generation of PNA/DNA/PNA triplexes. Scarce information is available on DNA strand invasion of mixed purine-pyrimidine stretches and theirs possible use as molecules able to interact with transcription factors. With this aim, we compared the effects of DNA/DNA, DNA/PNA or PNA/PNA hybrid molecules mimicking the NF-kappaB binding sites of HIV-1 on LTR-driven in vitro transcription. The results allowed us to conclude that PNA/PNA molecules and DNA/PNA hybrids are capable of inhibiting transcription, like the DNA/DNA. We investigated the mechanisms by which PNA/PNA and DNA/PNA hybrids affect the transcription. The results suggest that DNA/PNA and PNA/PNA molecules inhibit transcription in distinct manner; the inhibitory effects are due to strand invasion in the case of PNA/PNA hybrids and decoy effects on transcription factors belonging the NF-kappaB/Rel family in the case of DNA/PNA hybrids. It is noteworthy that DNA/PNA hybrids are more resistant to nucleases than DNA/DNA hybrids.