Date of Award
Joan C. Edwards School of Medicine
Type of Degree
W. Elaine Hardman
Pier Paolo Claudio
B-cell chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. CLL is often diagnosed in the asymptomatic (early-stage) stages. However, approximately 50% of these patients will progress to advanced, symptomatic disease and require therapy. Current treatment options are limited due to progressive drug resistance and severe drug-induced toxicities which are often too toxic for the elderly or those with co-morbidities. Therefore, a non-toxic therapeutic intervention that could slow the progression of asymptomatic CLL to symptomatic CLL or enhance the effects of actively used chemo-therapeutic drugs in patients who require therapy would be clinically beneficial.
In our studies, we evaluated the use of omega-3 (n-3) fatty acids as therapeutic options for CLL utilizing both a clinical supplementation model (FWA #00002704) as well as a cell culture model. The primary objective of the initial study was to determine whether consumption of n-3 could suppress activation of nuclear factor kappa B (NF B) in lymphocytes from patients diagnosed with early stage CLL. The primary objective of the follow-up study was to evaluate whether n-3 eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) could enhance the chemo-sensitivity of CLL-derived cell lines EHEB and MEC-2 and pro-lymphocytic leukemiaderived cell line JVM-2 to anti-cancer drugs doxorubicin, vincristine or fludarabine in vitro.
ur initial study indicated that consumption of an EPA + DHA containing n-3 supplement 1) suppressed activation of NF B in lymphocytes from patients diagnosed with early stage CLL, 2) increased molar concentrations of n-3 in the plasma, 3) increased the chemosensitivity of lymphocytes to doxorubicin in an in vitro assay and 4) decreased the expression of 32 genes in lymphocytes. Targeting the NF B pathway is proposed as a therapy for CLL. Suppression of NF B activation by n-3 may slow the progression of the disease to symptomatic disease where therapy is required. However, a definitive clinical trial will be needed to determine if n-3 can slow the progression of CLL.
The aim of the second study was to expanding upon the chemo-sensitization capabilities of n-3. In these trials, cell-cycle analyses, Annexin-V assays, assays for malondialdehyde (a measure of lipid peroxidation) and DCF fluorescence assays (a measure of reactive oxygen species (ROS) generation) were performed to explore potential mechanism(s) through which enhanced chemo-sensitivity was achieved.
Results indicated that: 1) EPA and DHA differentially sensitized B-leukemic cell lines EHEB, JVM-2 and MEC-2 to doxorubicin, vincristine and fludarabine in vitro; 2) n-3 alone and with drug treatment increased cell death and induced G2/M arrest in a cell-type specific manner; 3) lipid peroxidation increased in the presence of n-3; 4) there was higher lipid peroxidation in MEC-2 cells in presence of DHA and doxorubicin than with either alone; 5) n-3 increased generation of ROS in MEC-2, and 6) the addition of vitamin-E abrogated the increase in ROS generation and chemo-sensitivity of MEC-2 to doxorubicin by DHA.
N-3 are a promising therapeutic intervention for the treatment of CLL with the capacity to potentially slow the progression of the disease and enhance the chemo-sensitivity of malignant cells to chemo-therapeutic drugs and warrants further investigation. Slowing the progression of the disease would be clinically beneficial. Enhanced chemo-sensitivity would be expected to increase drug efficacy and potential reductions in drug dosage and drug-induced toxicities.
Leukemia - Treatment.
Omega-3 fatty acids - Research.
Fahrmann, Johannes Francois, "Omega-3 Fatty Acids as Therapeutic Options for the Treatment of B-cell Chronic Lymphocytic Leukemia" (2013). Theses, Dissertations and Capstones. 586.