Regulatory effect of resveratrol and prednisolone on MDR1 gene expression in acute lymphoblastic leukemia cell line (CCRF‐CEM): An epigenetic perspective

Abstract

Chemotherapy is the most common method to treat leukemia as well as other types of human cancers. However, drug resistance has remained as the main challenge against the efficacy of treatments. Furthermore, having various adverse effects, chemotherapy drugs are becoming replaced by natural modalities for cancer therapy. In this regard, herbal components such as resveratrol and prednisolone have been identified to sensitize the leukemic cells to programmed cell death through a set of complex processes. In this study, we have examined DNA methylation on the human multidrug resistance gene 1 (MDR1) as a well-known marker for cellular drug resistance. We evaluated the effect of resveratrol and prednisolone on DNA methylation patterns of MDR1 gene promoter in the CCRF-CEM cell line as a representative for acute lymphoblastic leukemia. The study was aimed to clarify whether the MDR1 gene expression is regulated via DNA promoter methylation as a potential underlying mechanism, following exposure to resveratrol and prednisolone. Our data revealed that despite a strong influence to down-regulate the MDR1 expression, Resveratrol and Prednisolone did not alter the methylation pattern, suggesting other regulatory mechanisms in controlling the MDR1 expression in CCRF-CEM cell line. Unchanged status of DNA methylation of MDR1 gene may suggest that Resveratrol and Prednisolone causes the gene expression changes through a distinct mechanism which requires further studies to be understood. A more detailed understanding of the mechanisms beyond the regulation of the genes involved in cancer formation will help to design novel therapeutic strategies to fight the human cancers.

Resveratrol suppresses melanoma growth by promoting autophagy through inhibiting the PI3K/AKT/mTOR signaling pathway

“…Resveratrol (RV) is a natural polyphenolic phytoalexin derived from peanuts, red grape skins and red wine (5). Emerging evidence suggests that RV is biologically versatile and confers the ability to protect against oxidative stress, malignancies and angiogenesis (6)(7)(8). The anti-malignant properties of RV arise from its ability to inhibit the PI3K/AKT signaling pathway (9), reduce glucose absorbance and metabolism (10), initiate apoptosis and autophagy (11), and regulate microRNA expression (12).…”

Protective Effects of Grape Molasses and Resveratrol Against DMBA Induced Oxidative Stress in Rat Ovarian Tissues

“…It suppresses cyclooxygenase-2 (COX-2) and lipid peroxidation. Thus, resveratrol shows different pharmacological functions such as antiangiogenic, antioxidant, antitumor and cardio-protective and anticancer (Zadi et al, 2018;Al Fatease et al, 2019;.…”

Apoptosis Induced by Prednisolone Occurs without Altering the Promoter Methylation of BAX and BCL-2 Genes in Acute Lymphoblastic Leukemia Cells CCRF-CEM

“…By inducing pre-apoptotic BCL-2 proteins, including BAX proteins, GC exacerbates the expression of the anti-apoptotic BCL-2 protein by causing caspase cascade and inducing apoptosis in the cell line of lymphoblastic leukaemia (Ghasemi et al, 2018). Adjusting gene expression through epigenetics, especially regulation through methylation, is one of the key aspects of regulation of gene expression and gene operation, and this regulatory phenomenon is also true for regulator genes of apoptosis' pathway (Azimi et al, 2015;Zadi Heydarabad et al, 2018). In other words, epigenetic modifications, especially methylation, can contribute to the balance between the expression of pre-apoptotic and anti-apoptotic proteins, which this epigenetic regulatory phenomenon in cancer cells can undergo a regulatory change and induce resistance to apoptosis against chemotherapy and anticancer factors (Garcia-Manero et al, 2002).…”

“…The outbreak of ALL in the world is roughly 5 per 100,000 populations per year (Estey and Döhner, 2006;Yousefi et al, 2016;Ahani-Nahayati et al, 2018). ALL patients, despite chemotherapy drugs, usually suffer from the side effects of these chemotherapy drugs and the risk of recurrence of the disease (Zadi Heydarabad et al, 2018). Apoptosis is a planned death that usually takes place to harmonize a balance between production and cell death of cells even in normal cells and is needed to maintain cellular homeostasis, a regulatory disorder that causes this disease including cancer (Hervouet et al, 2013).…”

“…On the other hand, the regulation of gene expression through epigenetics, especially regulation through methylation, is one of the key aspects of regulation of gene expression and the function of genes, which is also applied to regulator genes of the apoptosis' pathway. The phenomenon of epigenetic regulation in cancer cells can undergo a change in regulation and induces resistance to apoptosis against chemotherapy and anticancer agents (Hervouet et al, 2013;Zadi Heydarabad et al, 2018). Moreover, the development of analytical tools and extensive analysis of the genome emphasized a great deal on the prevalence of epigenetic changes in cancer.…”