Effects of the Phytopolyphenol Resveratrol as a Therapeutic Adjunct in Sickle Cell Disease (SCD) and β-thalassemia Management

Abstract

Sickle Cell Disease (SCD) and β-thalassemia are among the most common forms of hemoglobinopathy and life-threatening genetic diseases worldwide, necessitating the need for more effective and cost-effective therapies to treat these disorders. SCD occurs due to a single amino acid substitution of Valine for Glutamic acid in the β-chain subunit to form the sickle cell (HbS) variant. Hydroxyurea (HU) is currently the only disease modifying drug approved for SCD, while advances in gene editing processes have also recently been introduced but their clinical use is not yet widely therapeutically available. HU is a ribonucleotide reductase inhibitor and fetal hemoglobin (Hb F; α2γ2) inducer that can reduce the clinical symptoms and frequency of hospitalizations for SCD, but it falls short of being a curative therapy and must be continued indefinitely in SCD patients. The efficacy of HU in the management of thalassemia and SCD is generally attributed to its limited ability to boost the levels of fetal hemoglobin (Hb F, α2γ2) in RBCs, and provide a partially protective mechanism for the sickle reaction which ultimately damages the blood vessels, thereby contributory to the major pathophysiologic clinical signs and symptoms and decreased lifespan associated with the SCD disorder. Thus, we propose that partial amelioration of SCD hemoglobin (HbS) with fetal hemoglobin via pharmacologic effects of trans-resveratrol (RSV), a naturally occurring
phytochemical, may become a benefit to the patient since HbF is not susceptible to the disordered intracellular VO2-linked hemoglobin (HbS) polymerization often referred to as the sickling reaction during HbS deoxygenation. Accordingly, RSV would thereby limit the subsequent vessel damage due to small vessel occlusion which occurs due to HbS and thus should be able to improve patient outcomes by reducing the magnitude of ROS damage in addition to diminishing the ratio of cells that are susceptible to sickling reactions vs. the sickle-protected fetal-hemoglobin containing cells. In addition, RSV may also provide beneficial impacts on the sickle cell anemia (SCA) by prolonging erytrocyte survival that typically accompanies the disorder. Thus, RSV may also be able to partially correct the effects linked to the globin chain imbalance in SCD patients, while at the same time facilitating oxygen transport to myoglobin in peripheral tissues due to a more favorable oxygen- delivering capacity than is observed in adult hemoglobin. Thus, in conclusion, RSV may be a useful and cost-effective phytochemical adjunct in the treatment of SCD and β-thalassemia, the two major heritable hemoglobinopathies of humans.