Effects of polyunsaturated fatty acids on the efficacy of antineoplastic agents toward L5178Y lymphoma cells

Kinsella, John E.; Black, J. Mark

doi:10.1016/0006-2952(93)90447-5

Cited by 26 publications

(13 citation statements)

References 12 publications

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“…6a). Enhancement of doxorubicin efficacy by DHA has been reported for other in vitro tumor models [41][42][43] and in a dog model of lymphoma. 44 In lung cancer cells, DHA enhances the effects of cisplatin 45 and may partly reverse vincristine resistance in neuroblastoma cells.…”

Section: Discussionmentioning

confidence: 97%

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Lindskog

Gleissman

Ponthan

et al. 2006

Intl Journal of Cancer

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Docosahexaenoic acid (DHA) is an x-3 polyunsaturated fatty acid vital for the developing nervous system and significantly decreased in neuroblastoma cells compared to nontransformed nervous tissue. We investigated whether supplementation of DHA affects the susceptibility of neuroblastoma cells to oxidative stress generated endogenously and in response to cytotoxic therapy. DHA, but not the monounsaturated oleic acid (OA), induced dose-and timedependent neuroblastoma cell death. DHA supplementation was associated with depolarization of the mitochondrial membrane potential, production of reactive oxygen species (ROS) and accumulation of DNA in sub-G1 phase of the cell cycle. The antioxidant, vitamin E, inhibited mitochondrial depolarization and subsequent cell death induced by DHA, whereas, the mitochondrial pore inhibitor, cyclosporin A, partly inhibited DHA-induced neuroblastoma cell death. Depletion of glutathione by L-buthioninesulfoximine significantly enhanced the cytotoxic effects of DHA. Nontransformed fibroblasts were not substantially affected by DHA. DHA, but not OA, significantly enhanced the cytotoxicity of cisplatin, doxorubicin and irinotecan both in chemosensitive and in multidrug-resistant neuroblastoma cells. DHA potently sensitized neuroblastoma cells to a clinically relevant concentration (1 lM) of arsenic trioxide (As 2 O 3 ) and enhanced the effect of the nonsteroidal antiinflammatory drug (NSAID), diclofenac. These findings provide experimental evidence that the x-3 fatty acid, DHA, is cytotoxic to drug-resistant neuroblastoma. The potent action of DHA with arsenic trioxide, NSAID and chemotherapeutic agents suggests clinical testing of this therapeutic concept in children with neuroblastoma. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 97%

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Lindskog

Gleissman

Ponthan

et al. 2006

Intl Journal of Cancer

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“…Omega 3 fatty acids have consistently been shown to enhance the sensitivity of various solid tumor cells to chemotherapy in vitro [7,8] and in vivo [9-11]. However, this has not been shown in CLL.…”

Section: Discussionmentioning

confidence: 99%

“…The ratio of omega 3 FAs to omega 6 FAs in the average western diet is heavily weighted in favor of omega 6 [5,6]. Omega 3 fatty acids have consistently been shown to enhance sensitivity of various solid tumor cells to chemotherapy in vitro [7,8] and in vivo [9-11]. However, it has not been shown whether n-3 can enhance the sensitivity of CLL to anti-cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

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

Fahrmann

Hardman

2013

Lipids Health Dis

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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.

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“…2,6,7 Furthermore, these fatty acids are also able to induce tumor apoptosis through cell cycle gene modulation, or to activate and induce cell death via both a mitochondrial-dependent and a bax-mediated, mitochondrial-independent pathway. 8-10 DHA has also been shown to increase the therapeutic effects of Imatinib 11 doxorubicin, mitomycin C and cyclophosphamide, 12,13 while enhancing arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant leukemia cells. 14 …”

Section: Introductionmentioning

confidence: 99%

Docosahexanoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell line

Yamagami¹,

Porada²,

Pardini³

et al. 2009

Cancer Biology & Therapy

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Acute myeloid leukemia (AML) is the most frequently diagnosed adulthood leukemia, yet current therapies offer a cure rate of less than 30%. This may be due in part to the fact that the leukemia-initiating cells in AML reside within the rare and highly primitive CD34+CD38- hematopoietic stem/progenitor cell (HSC) population that are often resistant to chemotherapy. Docosahexanoic acid (DHA), a major component of fish oil, has previously been shown to inhibit the induction and progression of breast, prostate and colon cancer, and increase the therapeutic effects of numerous chemotherapeutics, often by enhancing apoptosis. In the present studies, we investigated DHA's effect on the primitive and undifferentiated AML cell line KG1a, to explore the potential of this fatty acid to serve as adjuvant therapy for AML. Treatment of KG1a cells with DHA for 96 hours did not lead to maturation or cell cycle modification when compared to an untreated KG1a control (n = 4). However, DHA treatment of KG1a cells resulted in a progressive loss of viability, DNA fragmentation, and an increase in Annexin V expression, demonstrating DHA-induced apoptosis (n = 4). Moreover, expression of the pro-apoptotic protein Bax was increased, with resultant skewing in the Bax/bcl-2 ratio, providing a mechanistic explanation for the observed DHA-induced increase in apoptosis. Since we also show that DHA does not have a detrimental effect on normal hematopoiesis our results suggest that DHA could potentially serve as an well-tolerated adjuvant in the treatment of AML patients.

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Effects of polyunsaturated fatty acids on the efficacy of antineoplastic agents toward L5178Y lymphoma cells

Cited by 26 publications

References 12 publications

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

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

Docosahexanoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell line

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