Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia

Morad, Samy A.F.; Ryan, Terrence; Neufer, P. Darrell; Zeczycki, Tonya N.; Davis, Traci S.; MacDougall, Matthew R.; Fox, Todd E.; Tan, Su‐Fern; Feith, David J.; Loughran, Thomas P.; Kester, Mark; Claxton, David F.; Barth, Brian M.; Deering, Tye; Cabot, Myles C.

doi:10.1194/jlr.m067389

Cited by 30 publications

(27 citation statements)

References 60 publications

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“…Multiple studies investigate the use of exogenous short chain ceramides as potential therapeutics for cancer, especially in combination with other drugs 32 . Combination treatment with C6-ceramide and tamoxifen induces alternations in energy production and decreases expression of anti-apoptotic proteins in AML cells 33-35 . Blocking intracellular ceramide modifications as well as treating with exogenous ceramide using nanoliposomes both induced apoptosis in AML 36 .…”

Section: Background and Introductionmentioning

confidence: 99%

The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia

Tan

Pearson

Feith

2017

Expert Opinion on Therapeutic Targets

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Introduction Acute myeloid leukemia (AML) is the most common adult leukemia. Only a fraction of AML patients will survive with existing chemotherapy regimens. Hence, there is an urgent and unmet need to identify novel targets and develop better therapeutics in AML. In the past decade, the field of sphingolipid metabolism has emerged into the forefront of cancer biology due to its importance in cancer cell proliferation and survival. In particular, acid ceramidase (AC) has emerged as a promising therapeutic target due to its role in neutralizing the pro-death effects of ceramide. Areas covered This review highlights key information about AML biology as well as current knowledge on dysregulated sphingolipid metabolism in cancer and AML. We describe AC function and dysregulation in cancer, followed by a review of studies that report elevated AC in AML and compounds known to inhibit the enzyme. Expert opinion AML has a great need for new drug targets and better therapeutic agents. The finding of elevated AC in AML supports the concept that this enzyme represents a novel and realistic therapeutic target for this common leukemia. More effort is needed towards developing better AC inhibitors for clinical use and combination treatment with existing AML therapies.

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Section: Background and Introductionmentioning

confidence: 99%

The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia

Tan

Pearson

Feith

2017

Expert Opinion on Therapeutic Targets

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“…We have recently demonstrated that combination C6-ceramide-tamoxifen promotes a decrease in mitochondrial membrane potential and inhibits complex I respiration in KG-1 AML cells [73]. As damaged mitochondria stimulate increased ROS production [74], we propose that the active combinations presented herein share mitochondria as a common target and employ ROS.…”

Section: Discussionmentioning

confidence: 95%

“…Cytochrome c release from mitochondria was assessed as described [28, 35, 36]. Briefly, 2 × 10 6 cells/2 mL RPMI-1640 medium, 2.5% FBS medium, were seeded in 6-well plates and treated with selected agents for 18 h, after which 1 × 10 6 cells were removed and placed on ice in 0.1 mL of digitonin (Sigma, St. Louis, MO) (100 μg/mL in PBS, 100 mM KCl) for 3–5 min, until 95% of the cells were permeabilized (stain positive with 0.2% trypan blue).…”

Section: Methodsmentioning

confidence: 99%

“…Although tamoxifen and desmethyltamoxifen (DMT) have been shown effective in combination with C6-cermide in acute myeloid leukemia (AML) [28, 29], herein our aim was to discover alternatives to tamoxifen that would be void in antiestrogen activities. Additionally, having effective alternatives to tamoxifen would broaden the utility of ceramide as a cancer therapeutic.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, that DMT is effective in combination with C6-ceramide is noteworthy, as this predominant tamoxifen metabolite in humans exerts < 1% of the antiestrogenic activity of parent tamoxifen [30], indicating that traditional anti-estrogen pathways are not involved in cellular responses. Of clinical relevance, we have previously shown that the C6-ceramide-tamoxifen combination is non-toxic in peripheral blood mononuclear cells, indicative of a cancer-selective action [28]. …”

Section: Introductionmentioning

confidence: 99%

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Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer

Morad

Davis

MacDougall

et al. 2017

Biochemical Pharmacology

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The anticancer properties of ceramide, a sphingolipid with potent tumor-suppressor properties, can be dampened via glycosylation, notably in multidrug resistance wherein ceramide glycosylation is characteristically elevated. Earlier works using the ceramide analog, C6-ceramide, demonstrated that the antiestrogen tamoxifen, a first generation P-glycoprotein (P-gp) inhibitor, blocked C6-ceramide glycosylation and magnified apoptotic responses. The present investigation was undertaken with the goal of discovering non-anti-estrogenic alternatives to tamoxifen that could be employed as adjuvants for improving the efficacy of ceramide-centric therapeutics in treatment of cancer. Herein we demonstrate that the tamoxifen metabolites, desmethyltamoxifen and didesmethyltamoxifen, and specific, high-affinity P-gp inhibitors, tariquidar and zosuquidar, synergistically enhanced C6-ceramide cytotoxicity in multidrug resistant HL-60/VCR acute myelogenous leukemia (AML) cells, whereas the selective estrogen receptor antagonist, fulvestrant, was ineffective. Active C6-ceramide-adjuvant combinations elicited mitochondrial ROS production and cytochrome c release, and induced apoptosis. Cytotoxicity was mitigated by introduction of antioxidant. Effective adjuvants markedly inhibited C6-ceramide glycosylation as well as conversion to sphingomyelin. Active regimens were also effective in KG-1a cells, a leukemia stem cell-like line, and in LoVo human colorectal cancer cells, a solid tumor model. In summary, our work details discovery of the link between P-gp inhibitors and the regulation and potentiation of ceramide metabolism in a pro-apoptotic direction in cancer cells. Given the active properties of these adjuvants in synergizing with C6-ceramide, independent of drug resistance status, stemness, or cancer type, our results suggest that the C6-ceramide-containing regimens could provide alternative, promising therapeutic direction, in addition to finding novel, off-label applications for P-gp inhibitors.

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C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells

Jiang

Wang

Feng

et al. 2016

Appl Microbiol Biotechnol

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Sorafenib as an effective multikinase inhibitor has been approved for the clinical treatment against advanced hepatocellular carcinoma (HCC). HCC treatment requires usually combined therapy because of its complex pathogenesis. Ceramide has been confirmed to induce remarkable apoptosis in human tumor cells and has attracted increasing attention in investigations on combination therapy. In this paper, the anti-HCC effect of sorafenib combined with C2-ceramide was investigated on cell vitality, apoptosis, and migration, and the underlying mechanism was examined using flow cytometry and western blot. Bel7402 cells coincubated with sorafenib and C2-ceramide exhibited lower cell vitality and more irregular cellular morphology and cell cycle arrest. Sorafenib plus C2-ceramide stimulated significantly the production of reactive oxygen species (ROS) and mitochondrial depolarization, which promoted caspases-dependent cell apoptosis as illustrated by related protein expression including caspase 3, caspase 9, Bax, Bcl-2, and cytochrome c. Combination treatment of sorafenib and C2-ceramide inhibited obviously cell growth and proliferation via PI3K/AKT/mTOR and Erk signaling pathways. Furthermore, the combination treatment was proved to inhibit cell migration and epithelial-mesenchymal transition (EMT). These findings indicated that the combination of C2-ceramide and sorafenib provided synergistic inhibitory effects on HCC cells.

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Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia

Cited by 30 publications

References 60 publications

The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia

The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia

Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer

C2-ceramide enhances sorafenib-induced caspase-dependent apoptosis via PI3K/AKT/mTOR and Erk signaling pathways in HCC cells

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