Omega 3 fatty acids increase the chemo-sensitivity of B-CLL-derived cell lines EHEB and MEC-2 and of B-PLL-derived cell line JVM-2 to anti-cancer drugs doxorubicin, vincristine and fludarabine

Abstract

BackgroundB-Cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. Clinical treatment of CLL is often limited due to drug resistance and severe therapy-induced toxicities. We hypothesized that the omega 3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), would increase the sensitivity of malignant B-lymphocytes to anti-cancer drugs doxorubicin, vincristine and/or fludarabine in vitro and that increased sensitivity is achieved by alterations in cell-cycle progression leading to growth inhibition and/or enhanced cell death. We further postulate that enhanced sensitivity is dependent on the formation of lipid peroxides and to the generation of reactive oxygen species (ROS).MethodsIn the present study, B-CLL-derived leukemic cell lines EHEB and MEC-2 and the B-Prolymphocytic leukemic-derived (PLL) cell line JVM-2 were tested for in vitro sensitivity against doxorubicin, vincristine or fludarabine in the presence or absence of vehicle, arachidonic acid (omega 6), EPA or DHA. Cell cycle analysis and Annexin-V assays were performed to determine cell cycle progression and % apoptotic cells, respectively. Assays for malondialdehyde, a measure of lipid peroxidation, and DCF fluorescence assays, a measure of intracellular ROS, were performed to determine if enhanced sensitivity of cells to the drugs by n-3 was dependent on the formation of ROS.ResultsOur 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.ConclusionN-3’s are promising chemo-sensitizing agents for the treatment of CLL. Selective enhancement of chemo-sensitivity of EHEB, JVM-2 and MEC-2 to drugs by n-3 that is not dependent on increased lipid peroxidation and ROS generation indicates alternative mechanisms by which n-3 enhances chemo-sensitivity.

Oral fish oil positively influences nutritional‐inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long‐term survival: a randomised clinical trial

“…Fish oil containing 367 mg of EPA and 243 mg of DHA for 9 weeks was sufficient to alter the fatty acid composition of plasma lipid constituents, leading to an approximately two‐fold increment in the proportion of EPA and a 1.8‐fold increase for DHA. The same finding has been reported in previous studies .…”

A Critical Review on the Effect of Docosahexaenoic Acid (DHA) on Cancer Cell Cycle Progression

“…Only three studies were found reporting that DHA treatment affects transition through the S phase of the cell cycle. In the hepatocarcinoma cell line MHCC97L, 50 μM DHA was found to disrupt and prolong S phase transition [ 22 ]. In this experiment, cells were BrdU-labelled and DNA synthesis time, based on the relative movement of cells through the cell cycle, was measured.…”

“…The time to progress through S phase increased from 18 to 21 h after DHA treatment. In particular, the proportion of Jurkat leukemia cells in the S phase of the cell cycle (measured at 0 and 24 h) increased from 30% to 68% with 30 μM DHA treatment while G1 decreased (62% to 43%) [ 22 ]. Control cells had a larger proportion of cells moving to G2 than the DHA treatment (11% vs. 2%), suggesting that cells were continuing to move through the cell cycle compared to the DHA cells that were accumulating in S phase [ 20 ].…”

“…Cyclin E controls entry from late G1 to S phase and this is followed, as DNA synthesis begins, by an increase in Cyclin A and associated CDK2 Cyclin A. CDK2 protein expression was found to be lower in metastatic MHCC97L liver cells [ 22 ] and leukemia [ 20 ] cells treated with DHA. DHA also decreased Cyclin E protein expression and decreased COX-2 mRNA expression in MHCC97L cells [ 22 ].…”

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

“…Among them, three conjugates have entered clinical trials and hold a great potential to be applied in clinicals in the future, including docosahexaenoic acid (DHA)‐paclitaxel (PTX), elaidic acid‐cytarabine, and elaidic acid‐gemcitabine . The rational design of UFAs‐based conjugates can be attributed to the following aspects: (i) to enhance the stability of anticancer drugs, the conjugation of anticancer drugs with UFAs can protect the fragile groups of the parent drug from being metabolized in vivo; (ii) to improve lipophilicity of drugs, hydrophilic drugs cannot easily pass through the bilayer membrane via passive diffusion, resulting in poor bioavailability in target sites; (iii) to achieve natural targeting effects to tumors, several studies have suggested an increased fatty acid uptake in tumors as nutrient sources; (iv) to enhance the chemotherapeutic response of anticancer drugs, some UFAs could significantly sensitize anticancer drugs‐induced apoptosis of human tumor cells; and (v) to minimize side effects of anticancer drugs at high doses, low cytotoxicity and sustained release of the parent drugs make UFAs‐based anticancer conjugates reduced side effects. Therefore, developing advanced UFAs‐based DDS holds great potential for cancer therapy.…”