4-HPR-mediated leukemia cell cytotoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2

Morales, María–Celia; Pérez‐Yarza, Gorka; Rementeria, N. Nieto; Boyano, María-Dolores; Apraiz, Aintzane; Gómez-Muñoz, Antonio; Pérez-Andrés, Encarna; Asumendi, Aintzane

doi:10.1080/10715760701218558

Cited by 30 publications

(28 citation statements)

References 49 publications

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“…For example, in prostate cancer cells, 4-HPR activates SPT [26], whereas in neuroblastoma cells 4-HPR can elevate ceramide levels by de novo and SMase-directed avenues [27]. Similar diversity has been reported in acute lymphoblastoid leukemia (ALL), wherein 4-HPR activates temporally early SMase activity followed by downstream de novo synthesis [17]. Adding to the complexity of targets for generation of ceramide by 4-HPR are the mosaic events involved in intracellular metabolism of ceramide, events that can dictate 4-HPR efficacy.…”

Section: Introductionmentioning

confidence: 90%

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Dynamics of ceramide generation and metabolism in response to fenretinide – Diversity within and among leukemia

et al. 2015

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Fenretinide, N-(4-hydroxyphenyl)retinamide, (4-HPR), a synthetic retinoid, owes its cancer-toxic effects in part to the generation of ceramide, a potent tumor-suppressing sphingolipid. As such, 4-HPR has garnered considerable interest as a chemotherapeutic. Cancer cells, however, via various metabolic routes, inactivate ceramide, and this can limit 4-HPR efficacy. As relatively little is known regarding 4-HPR-induced ceramide management in acute myelogeneous leukemia (AML), we undertook the present study to evaluate the impact of 4-HPR on ceramide production, metabolism, and cytotoxicity. In KG-1, HL-60, and HL-60/VCR (multidrug resistant) human leukemia cells, 4-HPR induced 15-, 2-, and 20-fold increases in ceramide (measured using [3H]palmitic acid), respectively. By use of specific inhibitors we show that ceramide was produced by sphingomyelinase and de novo pathways in response to 4-HPR exposure. HL-60/VCR cells metabolized ceramide to glucosylceramide (GC). 4-HPR exposure (1.25 – 10 μM) reduced viability in all cell lines, with approximate IC50’s ranging from 1 – 8.0 μM. Reactive oxygen species (ROS) were generated in response to 4-HPR treatment, and the concomitant cytotoxicity was reversed by addition of vitamin E. 4-HPR was not cytotoxic nor did it elicit ceramide formation in K562, a chronic myeloid leukemia cell line; however, K562 cells were sensitive to a cell-deliverable form of ceramide, C6-ceramide. Treatment of Molt-3, an acute lymphoblastic leukemia cell line, with 4-HPR revealed moderate ceramide production (5-fold over control), robust conversion of ceramide to GC and sphingomyelin, and resistance to 4-HPR and C6-ceramide. In conclusion, this work demonstrates diversity within and among leukemia in 4-HPR sensitivity and ceramide generation and subsequent metabolism. As such, knowledge of these metabolic pathways can provide guidance for enhancing ceramide-driven effects of 4-HPR in treatment of leukemia.

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Section: Introductionmentioning

confidence: 90%

“…In some instances, ceramide production is responsible for ROS generation [17], events that message downstream apoptotic responses. However, in survival mode, cancer cells dampen ceramide potency via glycosylation, producing glucosylceramide (GC).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of ceramide generation and metabolism in response to fenretinide – Diversity within and among leukemia

et al. 2015

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“…Since its first synthesis in 1960s, several articles have been published trying to elucidate the molecular mechanisms associated with 4-HPR effects (Mody and Mcilroy, 2014). It had been thought that 4-HPR would elevate Cer by activation of serine palmitoyl transferase and Cer synthase (Maurer et al, 2000;Morales et al, 2007). However, it was later established that dhCer rather than Cer was the actual accumulating lipid, whose buildup was caused by 4-HPR inhibition of Des1 Wang et al, 2008).…”

Section: Fenretinide (4-hpr)mentioning

confidence: 97%

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

Casasampere

Ordóñez

Pou

et al. 2016

Chemistry and Physics of Lipids

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“…5). Interestingly, in CCRF-CEM acute lymphoblastoid leukemia cells, Morales et al [44] showed that single agent 4-HPR was sufficient to trigger cytotoxicity through ceramide-induced mitochondrial oxidative stress. These authors astutely suggested the potential of modulators of ceramide metabolism to enhance the effects of 4-HPR-based therapies, much like our study demonstrates.…”

Section: Discussionmentioning

confidence: 99%

Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia—Impact on enzyme activity and response to cytotoxics

Morad

Tan

Feith

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The triphenylethylene antiestrogen, tamoxifen, can be an effective inhibitor of sphingolipid metabolism. This off-target activity makes tamoxifen an interesting ancillary for boosting the apoptosis-inducing properties of ceramide, a sphingolipid with valuable tumor censoring activity. Here we show for the first time that tamoxifen and metabolite, N –desmethyltamoxifen (DMT) block ceramide glycosylation and inhibit ceramide hydrolysis (by acid ceramidase, AC) in human acute myelogenous leukemia (AML) cell lines and in AML cells derived from patients. Tamoxifen (1-10 μM) inhibition of AC in AML cells was accompanied by decreases in AC protein expression. Tamoxifen also depressed expression and activity of sphingosine kinase 1 (SphK1), the enzyme catalyzing production of mitogenic sphingosine 1-phosphate (S1-P). Results from mass spectroscopy showed that tamoxifen and DMT, i ) increased the levels of endogenous C16:0- and C24:1 ceramide molecular species, ii) nearly totally halted production of respective glucosylceramide (GC) molecular species, iii ) drastically reduced levels of sphingosine ( to 9% of control), and iv ) reduced levels of S1-P by 85%, in vincristine-resistant HL-60/VCR cells. Co-administration of tamoxifen with either N-(4-hydroxyphenyl)retinamide (4-HPR), a ceramide-generating retinoid, or a cell-deliverable form of ceramide, C6-ceramide, resulted in marked decreases in HL-60/VCR cell viability that far exceeded single agent potency. Combination treatments resulted in synergistic apoptotic cell death as gauged by increased Annexin V binding and DNA fragmentation and activation of caspase-3. These results show the versatility of adjuvant triphenylethylene with ceramide-centric therapies for magnifying therapeutic potential in AML. Such drug regimens could serve as effective strategies, even in the multidrug resistant setting.

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4-HPR-mediated leukemia cell cytotoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2

Cited by 30 publications

References 49 publications

Dynamics of ceramide generation and metabolism in response to fenretinide – Diversity within and among leukemia

Dynamics of ceramide generation and metabolism in response to fenretinide – Diversity within and among leukemia

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia—Impact on enzyme activity and response to cytotoxics

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