Predictors of severity and new treatments for bone marrow neoplasias: mechanisms by which quercetin, epigallocatechin 3-gallate, gallic acid, turmeric, artemisimine and derivatives modulate epigenetic changes and energy metabolism in myelodysplasia

Abstract

Bone marrow neoplasias are aggressive disorders with low healing potential. As the incidence of Cancer increases with age, a growing number of older individuals are receiving therapy for Cancer and frequently in intensive modalities. As these older patients tend to present comorbidities, treatment decisions can often become difficult due to their fragile physical state which may affect therapy tolerability and efficiency against Cancer. The toxicity related to the treatment and long periods of hospitalization, often required, have a profound impact upon the quality of life of these patients. However, most elderly individuals and family members consider quality of life a priority. Additionally, extended treatments deplete the financial resources of both public and private health systems, and the extra costs also deplete the family´s financial reserves.In light of the foregoing, the present study will address novel therapeutic forms and severity predictors which could aid in therapy decision taking of the following bone marrow neoplasias: Acute Myeloid Leukemia (AML) Myelodysplastic Syndromes (MDS), Multiple Myeloma (MM) and Primary Myelofibrosis (PMF). These disorders have a common characteristic which is the fatal course of the disease and the lack of efficient therapeutic options, where bone marrow transplantation represents the only curative therapy or therapy capable of extending survival, despite not being indicated for older patients or those with many comorbidities. Therefore, a number of issues could be clarified by this study: What would be the effect of natural products, which have been demonstrated to be inductor agents of cell death or cell cycle arrest, upon the treatment of these disorders? These compounds have a known action of inducing or inhibiting Reactive Oxygen Species (ROS) and/or nitric oxide and can have a direct effect upon the induction of neoplasia cell death or modulate cell immunity. Would elderly patients have a better survival and quality of life were they to be treated with less aggressive therapies with less side effects? Could mesenchymal cells or metformin reduce bone marrow fibrosis? Would dendritic cell vaccines for AML and MM patients in remission, be an alternative for reducing disease recurrence? Could severity markers for the aforementioned disorders, identified in our previous studies, be the targets of specific therapies? Would the production of universal in vitro platelets to improve the support therapy of these patients be possible? This choice of investigation is a result of our dissatisfaction in observing that most patients with bone marrow neoplastic disorders are not candidates for last-generation treatments. Furthermore, the lack of hospital beds and the impossibility of using high cost antibiotics and immunobiologicals in the unified public health system (SUS) point to the need of performing high level research to seek alternatives to enable us, in the short-term, to face the reality of many patients who have no access to clinical studies with new high cost drugs, not only in Brazil, but throughout the World. For this investigation, we will carry out pre-clinical trials, using leukemia, myelodysplastic and xenogeneic tumor animal models, and phase I and II clinical studies. We will further standardize the production method of universal platelets, to enable better support for patients with severe bone marrow failure in consequence of hematologic neoplasia. (AU)