Docosahexaenoic acid enhances arsenic trioxide–mediated apoptosis in arsenic trioxide–resistant HL-60 cells

Sturlan, Sanda; Baumgartner, M.; Roth, Erich; Bachleitner‐Hofmann, Thomas

doi:10.1182/blood-2002-08-2391

Cited by 83 publications

(80 citation statements)

References 46 publications

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“…In addition, 10 μg/ml JFA contains 3.6 μM oleic acid. Considering that a previous study showed that 25 μM oleic acid did not affect the cell viability of HL-60 cells 15 , we deemed it unlikely that oleic acid in JFA was responsible for the cytotoxic effects on HL-60 cells. As shown in Fig.…”

Section: Figmentioning

confidence: 99%

Induction of Apoptotic Cell Death in HL-60 Cells by Jacaranda Seed Oil Derived Fatty Acids

et al. 2013

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Section: Figmentioning

confidence: 99%

Induction of Apoptotic Cell Death in HL-60 Cells by Jacaranda Seed Oil Derived Fatty Acids

et al. 2013

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“…5,19,20 BSO modulates the cellular glutathione system and can significantly potentiate the effects of As 2 O 3 , converting arsenic-resistant cell lines to a sensitive phenotype. 21,22 Although in vivo effects have been reported for this combination, 23 the observed additive toxicity may not be selective for cancer cells, and BSO itself has not been successfully developed for clinical use.…”

Section: Introductionmentioning

confidence: 99%

Trolox enhances the anti-lymphoma effects of arsenic trioxide, while protecting against liver toxicity

et al. 2007

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Arsenic trioxide (As 2 O 3 ) is an effective therapy in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the higher concentrations required to induce apoptosis. We have reported that trolox, an analogue of a-tocopherol, increases As 2 O 3 -mediated apoptosis in a variety of APL, myeloma and breast cancer cell lines, while nonmalignant cells may be protected. In the present study, we extended previous results to show that trolox increases As 2 O 3 -mediated apoptosis in the P388 lymphoma cell line in vitro, as evidenced by decrease of mitochondrial membrane potential and release of cytochrome c. We then sought to determine whether this combination can enhance antitumor effects while protecting normal cells in vivo. In BDF 1 mice, trolox treatment decreased As 2 O 3 -induced hepatomegaly, markers of oxidative stress and hepatocellular damage. In P388 tumor-bearing mice, As 2 O 3 treatment prolonged survival, and the addition of trolox provided a further significant increase in lifespan. In addition, the combination of As 2 O 3 and trolox inhibited metastatic spread, and protected the tumor-bearing mice from As 2 O 3 liver toxicity. Our results suggest, for the first time, that trolox might prevent some of the clinical manifestations of As 2 O 3 -related toxicity while increasing its pro-apoptotic capacity and clinical efficacy in hematological malignancies.

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“…[49][50][51][52] Studies suggest a broad spectrum of antileukemic activity for As 2 O 3 because of its ability to increase intracellular ROS production. 53 In As 2 O 3 -sensitive cells, such as the APL-derived cell line NB-4, increased intracellular levels of ROSs lead to collapse of the mitochondrial membrane potential, activation of the caspases, and apoptosis. However, cells with intracellular antioxidant defense mechanisms, such as the acute myeloid leukemia (AML)-derived cell line HL-60, are resistant to As 2 O 3 .…”

Section: Discussionmentioning

confidence: 99%

“…HL-60, an acute myeloid leukemia cell line that is resistant to clinically relevant doses of arsenic, shows a 90% reduction in viability along with an increase in apoptosis, an increase in intracellular reactive oxygen species (ROSs) and lipid peroxidation, as well as an up-regulation of Bax when treated with a combination of arsenic and DHA. 30 Further, treatment with oleic acid, a monounsaturated fatty acid that is not susceptible to lipid peroxidation, did not enhance the effect of arsenic treatment. 31 In breast cancer cells, the addition of DHA results in an increase in malondialdehyde, an end product of lipid peroxidation, which increases sensitivity to doxorubicin treatment through oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Emodin and DHA potently increase arsenic trioxide interferon-α–induced cell death of HTLV-I–transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1

Brown

Bellon

Nicot

2006

Blood

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Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disease of poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). The use of arsenic trioxide (As 2 O 3 ) has been shown to effectively treat acute promyelocytic leukemia (APL) with greater than 80% of patients achieving complete remission. The combination of arsenic and interferon has also shown promising results in the treatment of ATL.The requirement for slow dosage increases of arsenic and the time required to achieve a pharmacologic active dose in patients is a major obstacle because median survival of patients with ATL is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon ␣ (As/IFN-␣) with emodin and DHA on cellcycle arrest and cell death of HTLV-Iinfected cells. Importantly, we found that clinically achievable doses of DHA and emodin allowed for reduced arsenic concentrations by 100-fold while still remaining highly toxic to tumor cells. Our data provide a rationale for combined use of As/IFN-␣ with emodin and DHA in patients with ATL refractory to conventional therapy. ( IntroductionAdult T-cell leukemia (ATL) is associated with a poor clinical prognosis, and treatment of patients using conventional chemotherapy has limited benefit given that HTLV-I cells are resistant to conventional anticancer, apoptosis-inducing agents. 1-3 Cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) protocol has a reported 17% rate of remission but a predicted survival of less than 15% after 3 years. [4][5][6] Some success has been reported in treating ATL with a combination of zidovudine (AZT) and IFN-␣. [7][8][9][10] However, this success is fleeting as many patients relapse, because response to therapy requires the presence of a transcriptionally active p53 gene. 11 Other treatments include bone marrow transplantation, 12-14 topoisomerase inhibitors, 15,16 anti-Tac monoclonal antibody, 17 inhibitors of NF-kB 18,19 and proteasome inhibitors. 20 Arsenic trioxide in combination with IFN-␣ is very effective in treating APL [21][22][23] and showed promising results in the treatment of patients with ATL. [24][25][26][27][28][29] However, differences in sensitivity to arsenic, as well as the toxicity associated with its use, require a slow dose increase in vivo, and treatment may need to be discontinued in some patients with ATL. Thus, it is worthwhile to investigate the effectiveness of docosahexaenoic acid (DHA) a nontoxic -3 polyunsaturated fatty acid found in fish oil. HL-60, an acute myeloid leukemia cell line that is resistant to clinically relevant doses of arsenic, shows a 90% reduction in viability along with an increase in apoptosis, an increase in intracellular reactive oxygen species (ROSs) and lipid peroxidation, as well as an up-regulation of Bax when treated with a combination of arsenic and DHA. 30 Further, treatment with oleic acid, a monounsaturated fatty acid that is not susceptible to lipid peroxidation, did not en...

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Docosahexaenoic acid enhances arsenic trioxide–mediated apoptosis in arsenic trioxide–resistant HL-60 cells

Cited by 83 publications

References 46 publications

Induction of Apoptotic Cell Death in HL-60 Cells by Jacaranda Seed Oil Derived Fatty Acids

Induction of Apoptotic Cell Death in HL-60 Cells by Jacaranda Seed Oil Derived Fatty Acids

Trolox enhances the anti-lymphoma effects of arsenic trioxide, while protecting against liver toxicity

Emodin and DHA potently increase arsenic trioxide interferon-α–induced cell death of HTLV-I–transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1

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