Affiliation of authors: Breast Cancer Research Program and Chemotherapeutics, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA.
Correspondence to: Myles C. Cabot, Ph.D., Breast Cancer Research Program and Chemotherapeutics, John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Blvd., Santa Monica, CA 90404 (e-mail: cabot{at}jwci.org).
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ABSTRACT |
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DRUG RESISTANCE |
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CERAMIDE FORMATION |
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CERAMIDE CELL SIGNALING AND APOPTOSIS |
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Ceramide-mediated cell signaling has been shown to contribute to cell cycle arrest, terminal cell differentiation, and apoptosis (4348), as well as to cell proliferation (49). Ceramide and other sphingolipids act as second messengers modifying a number of target proteins that induce a cascade of enzymatic and transcriptional activity. One ceramide target protein that has been characterized extensively is ceramide-activated protein kinase (50,51). Other downstream target proteins include ceramide-activated protein phosphatases (52,53), the small guanosine triphosphate-binding protein raf-1, and the atypical protein kinase C(54). These proteins appear to contribute to proliferation and, possibly, to inflammation by recruiting the mitogen-activated protein kinase pathway (55), which has been described in detail (56). These proteins also may recruit the stress-activated protein kinase/c-JUN N-terminal kinase (SAPK/JNK) pathway (56). The SAPK/JNK pathway stimulates activity of AP-1 nuclear factors (e.g., c-Jun) that promote transcriptional activation of various genes and that appear necessary to apoptosis (57). Studies have shown that disrupting the SAPK/JNK/AP-1 pathway with antisense oligonucleotides to either JNK-1 or c-jun (57) or with dominant negative c-jun mutants blocks ceramide-mediated apoptosis (58).
Ceramide-induced cell death proceeds by at least two pathways. One pathway is transcriptionally dependent, and the other is transcriptionally independent. The transcriptionally dependent pathway is mediated by the interaction of members of the TNF superfamily of receptors (i.e., TNF- and CD95/APO-1/Fas receptors) (59) and their specific ligands. In the CD95 receptor pathway, ceramide is generated by acid sphingomyelinase in a complex series of steps (60). This involves several adapter molecules, such as the TNF receptor 1-associated death domain and the Fas-associated death domain (FADD or MORT1). Death domains of each of these adapter molecules are capable of binding with and potentially activating downstream protease caspases that affect apoptosis [reviewed in (44)]. This type of transcription-dependent ceramide signaling may be important in determining the cytotoxic response to certain chemotherapeutic agents. Activation of CD95/APO-1/Fas signaling by ceramide has been shown to mediate doxorubicin-induced apoptosis (61).
The transcription-independent pathway is characterized by the direct activation of acid sphingomyelinase by environmental stresses, such as ionizing radiation and oxidative damage (62). The subsequent production of ceramide, in turn, activates the SAPK/JNK apoptotic pathway. In addition, the transcriptionally independent formation of ceramide also may affect apoptosis-related proteins of the Bcl-2 family. Ceramide may alter the relationship between proapoptotic (i.e., Bax and Bad) and antiapoptotic (i.e., Bcl-2 and Bcl-XL) members of the Bcl-2 family of proteins that are associated with the mitochondrial membrane. Inhibitory proteins, such as Bcl-2, when overexpressed in cells, have the capacity to block ceramide-mediated cell death without altering ceramide generation (6365). By inducing the heterodimerization of proapoptotic proteins with antiapoptotic proteins, ceramide may reverse a cytoprotective signal (from Bcl-2) and initiate cell death. The loss of this cytoprotective signal leads to a loss of mitochondrial membrane integrity and the efflux of additional proapoptotic molecules, such as cytochrome c and apoptosis-inducing factor (39).
Both the transcriptionally dependent and independent pathways activate downstream molecules of the interleukin 1-converting enzyme family of caspase proteases, which affect apoptosis. A number of caspases may be activated in the various ceramide signaling pathways. Caspase-8 is the particular caspase associated with the TNF receptor-mediated signal and interacts directly with the adapter molecules FADD/MORT1. Caspase-9 and caspase-2 are mitochondrial-associated proteases and may be activated in either pathway. Both caspase-8 and caspase-9 recruit caspase-3. Ultimately, multiple caspases are activated, leading to proteosome-directed DNA fragmentation and cell death (66,67). The ceramide pathway is a complex system of signal reinforcement and magnification that has not been defined completely. There may be cross-talk at various levels of either the transcriptionally dependent or independent pathways, and nuclear transcription factors, phospholipases, reactive oxygen intermediates, and intracellular calcium may play relevant roles (48).
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CERAMIDE AND RESPONSE TO CHEMOTHERAPY |
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Some of the cytotoxic properties of vinca alkaloids (vincristine and vinblastine), widely used in the treatment of leukemia patients, may be due to their ability to increase cellular ceramide. Exposure of ALL-697 leukemia cells to vincristine causes apoptosis after a sustained increase in ceramide (65). The related alkaloid vinblastine also works by increasing cellular ceramide levels. Vinblastine concentrations as low as 1.5 nM cause a concomitant increase in ceramide levels and cell death in KB-31 human epidermoid carcinoma cells. However, concentrations as high as 1.0 µM have no effect on ceramide levels in the vinblastine-resistant counterpart KB-V-1 cells (73), again suggesting that drug resistance may be related to ceramide metabolism.
Paclitaxel inhibits microtubule depolymerization and is effective against a number of different solid tumors, including ovarian and breast cancers. Paclitaxel induces programmed cell death in a number of different cell types, including leukemia and breast cancer cells (7476). Studies have shown that the coadministration of paclitaxel with exogenous ceramide substantially inhibits cell proliferation and elicits apoptosis in a synergistic fashion in Jurkat T cells (75) and Tu138 head and neck squamous cell cancer (77). Moreover, studies have shown that the effects of paclitaxel are linked to the de novo synthesis of ceramide in MDA-MB-468 and MCF-7 breast cancer cells (Fig. 3, A, MCF-7 cells) (76,78) and that paclitaxel-dependent cytotoxicity was abrogated by blocking ceramide production with L-cycloserine, an inhibitor of ceramide synthesis (78).
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The synthetic retinoid 4-HPR elicits apoptosis in human prostate carcinoma cells through genesis of reactive oxygen species, nuclear retinoic acid receptors, or apoptosis-related genes (82). In addition, 4-HPR increases the level of intracellular ceramide in highly drug-resistant human neuroblastoma cell lines (83) and in the prostate cancer cell line LNCaP (Fig. 3, B, and our unpublished data). Because the expression of p53 protein is not affected by 4-HPR, the retinoid may form the basis for a novel p53-independent chemotherapy regimen targeting the ceramide pathway. In leukemia cells, 4-HPR but not retinoic acid activates ceramide formation and induces apoptosis (84). Simultaneous treatment of leukemia cells with 4-HPR and the ceramide synthase inhibitor fumonisin B1 decreases ceramide elevation and blocks induction of apoptosis.
DT388-GM-CSF, a fusion toxin consisting of a truncated diphtheria toxin linked to human granulocytemacrophage colony-stimulating factor (GM-CSF) (85), is toxic to acute myeloid leukemia progenitors bearing the GM-CSF receptor but not to normal marrow cell progenitors (86). The fusion toxin modulates drug resistance in vincristine-resistant HL-60 cells (87). Although one mechanism of action is inactivation of the expression of multidrug resistance proteins, we have shown that DT388-GM-CSF also is a potent agonist of ceramide formation in HL-60/VCR cells (Fig. 3, C). In these cells, ceramide is generated via hydrolysis of cellular sphingomyelin, suggesting a sphingomyelinase-governed response. In addition, we have shown that ceramide formation is followed by activation of caspase-9 and caspase-3 in this cell system (88).
Suramin, a polysulfonated naphthylurea introduced in the 1920s for the treatment of African trypanosomiasis, is synergistic with TNF- and doxorubicin in human prostate cancer cells (89). Synergy was noted at drug concentrations achieved clinically. A subsequent study (90) showed that bcl-2-transfected prostate cancer cells were resistant to apoptosis induced by doxorubicin; use of a doxorubicin/suramin combination circumvented this resistance. Gill and Windebank (91) reported that suramin disrupts glycolipid metabolism and elicits apoptosis after elevation of ceramide in various cancer cell models. In animal studies, suramin slows the growth of DU145 prostate cancer xenografts in nude mice (92), and it is currently in clinical trials for breast and prostate cancers (9395).
Several other cytotoxic agents have been shown to elevate cellular ceramide levels. Tepper et al. (96) reported a threefold elevation of ceramide levels in Jurkat T cells whose DNA has been damaged by exposure to the topoisomerase II inhibitor etoposide. Etoposide increases cellular ceramide levels de novo via activation of serine palmitoyltransferase (97). GW1843, a thymidylate synthase inhibitor in clinical development, causes Molt-4 leukemic T cells to undergo apoptosis with activation of both acidic and neutral sphingomyelinases and ceramide production (98). In this study, the kinetics of ceramide formation were consistent with its role in signaling apoptosis. 1,25-Dihydroxyvitamin D3 stimulates hydrolysis of sphingomyelin in leukemia cells (43) and in keratinocytes (99). It also inhibits the growth of prostate adenocarcinoma cells (100), but it is not known whether ceramide is involved in growth inhibition. Two nucleoside analogues, fludarabine and 1--D-arabinofuranosylcytosine, promote ceramide generation in leukemia cells. Exposure of HL-60 cells to 1-
-D-arabinofuranosylcytosine causes a time-dependent and dose-dependent increase in ceramide (37) that follows activation of neutral sphingomyelinase. Treatment of B cells (from patients with chronic B-cell lymphocytic leukemia) with fludarabine results in ceramide elevation and in killing by both apoptotic and nonapoptotic mechanisms (101). The topoisomerase I inhibitor irinotecan (CPT-11) increases ceramide levels in 4B1 mouse fibroblasts (102) and in HT-29 human colon cancer cells (our unpublished data). CPT-11 cytotoxicity is blocked by treatment with the ceramide synthesis inhibitor fumonisin B1 [(102); our unpublished data]. Treatment of HL-60 cells with sodium nitroprusside, a nitric oxide donor, is associated with activation of magnesium-dependent neutral sphingomyelinase, generation of ceramide, and apoptosis (103). To our knowledge, this work is the first to show a relationship between sphingolipid metabolites and nitric oxide-mediated cell death signaling; however, the response may be cell type specific.
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CERAMIDE AND RESPONSE TO RADIOTHERAPY |
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Cellular resistance to ionizing radiation also may be linked to impaired ceramide production or defective ceramide signaling (105,106). Michael et al. (105) demonstrated a direct relationship between resistance to radiation-induced apoptosis and defective ceramide signaling in Burkitt's lymphoma. Acquired defects in ceramide cell death signaling may contribute to the development of radioresistant thymoma cell lines (107). Ceramide also has been shown to participate in molecular events that govern UV radiation-induced apoptosis (108). Moreover, defective radiation-induced ceramide generation and cellular resistance to radiation treatment in sphingomyelinase knockout mice and in patients with NiemannPick disease (characterized by a congenital deficiency in sphingomyelinase) can be corrected by transfection of the human acidic sphingomyelinase gene (34).
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CERAMIDE METABOLISM AND MULTIDRUG RESISTANCE |
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The cytotoxic potential of many cancer drugs is related to activation of signal transduction pathways that lead to apoptosis (111113). Disruption of this process renders tumor cells drug resistant. TNF--resistant MCF-7 breast cancer cells have been characterized by the inability of their neutral or acidic sphingomyelinases to generate ceramide (20). Using rhabdomyosarcoma cells, Bourteele et al. (114) showed that TNF-
-induced apoptosis is preceded by a multiphasic increase in intracellular ceramide and inhibition of two ceramide-metabolizing enzymes, GCS and sphingomyelin synthase. In addition, acid ceramidase, which catalyzes ceramide breakdown, is overexpressed in prostate tumor tissue and in prostate tumor cell lines (115). This enzyme may play a role in later stage hormone-insensitive, chemotherapy-refractory prostate cancer. Overexpression of acid ceramidase also protects cells from TNF-
-induced death, whereas pharmacologic suppression of acid ceramidase by N-oleoylethanolamine restores ceramide accumulation and sensitivity to cytokines (116). These results suggest that the ability of cells to limit ceramide metabolism contributes to chemosensitivity.
Evidence is mounting that the accumulation of a glycosylated form of ceramide, glucosylceramide, may play an important role in the development of drug resistance. Glucosylceramide is an intermediate metabolite in the synthesis and degradation of the more complex gangliosides (Fig. 1, right). A number of drug-resistant cancer cell lines accumulate this noncytotoxic metabolite (18,19). Drug-resistant MCF-7-AdrR breast cancer and KB-V-1 cutaneous cancer cells have higher levels of glucosylceramide than their drug-sensitive counterparts, MCF-7 and KB-31 (19). The human ovarian adenocarcinoma cell line NIH:OVCAR-3, established from a patient resistant to doxorubicin, melphalan, and cisplatin, also expresses high levels of glucosylceramide (19). Moreover, analysis of tumors from selected cancer patients who failed to respond to chemotherapy treatment demonstrated elevated glucosylceramide levels (19). These findings suggest that elevated glucosylceramide levels in cancer cells or in tumors represent a marker for a drug-resistant phenotype.
The level of activity of GCS, which converts ceramide to glucosylceramide, may determine the multidrug resistance phenotype in cancer cells. To better characterize the influence of GCS on multidrug resistance, we used a retroviral "tetracycline-on" expression system to introduce the GCS gene into drug-sensitive MCF-7 cells. The resulting cell line MCF-7/GCS expresses an 11-fold higher level of GCS activity, is resistant to doxorubicin and exogenous ceramide (21), and is also resistant to TNF--induced cell death (22). Lipid metabolism studies confirmed that TNF-
causes an increase in ceramide in MCF-7 cells but causes an increase in glucosylceramide in resistant MCF-7/GCS cells. In addition, TNF-
exposure increases caspase activity in MCF-7 cells but not in MCF-7/GCS. Furthermore, resistance to doxorubicin and TNF-
in MCF-7/GCS cells is related to hyperglycosylation of ceramide and not to changes in the levels of P-glycoprotein, Bcl-2, or TNF receptor-1 expression (21,22). These results support the theory that GCS activity and the accumulation of cellular glucosylceramide are important to the development of chemotherapy resistance in cancer cells.
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CHEMOSENSITIZATION AND REVERSAL OF DRUG RESISTANCE BY REGULATING CERAMIDE METABOLISM |
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Several other hormone-modulating agents that are capable of altering drug resistance also retard cellular synthesis of glucosylceramide. Toremifene, an antiestrogen that is chemically and pharmacologically similar to tamoxifen, is also effective (126,131) and is being evaluated for reversing multidrug resistance in renal cell cancer patients (132). The antiprogestine mifepristone (RU486) inhibits proliferation and induces apoptosis in breast cancer cells (133). Mifepristone also inhibits glucosylceramide production (126) while sensitizing MCF-7-AdrR cells to the toxic effects of doxorubicin (72). Of interest, the combination of mifepristone and tamoxifen has been shown to elicit greater cell death than either agent alone when tested on MCF-7 breast cancer cells (134). The antifungal ketoconazole, which is structurally similar to tamoxifen, overcomes resistance to doxorubicin and vinblastine (135) and inhibits glucosylceramide synthesis (our unpublished data).
SDZ PSC 833 is a cyclosporin-based multidrug resistance modulator that appears to act via a P-glycoprotein mechanism (136). However, we have also shown that this agent is an effective inducer of ceramide formation (137). Investigators (138) have reported the antiproliferative effects of SDZ PSC 833 in drug-resistant cells, and our group (73,81) demonstrated that this agent's ability to increase cellular ceramide is associated with a progressive decline in cell survival. SDZ PSC 833 is active in the 1- to 5-µM range; in drug-sensitive MCF-7 breast cancer cells, SDZ PSC 833-induced ceramide generation is associated with decreased cell survival (137), independent of the expression of P-glycoprotein (139). SDZ PSC 833 increases vinblastine sensitivity in both P-glycoprotein-rich and P-glycoprotein-poor cancer cells (73). An example of the influence of SDZ PSC 833 on ceramide metabolism is shown in Fig. 3, D, with the human ovarian carcinoma cell line SKOV-3. Cells with enhanced capacity for ceramide glycosylation (18) are more resistant to SDZ PSC 833 than wild-type cells (81). A metabolic study (81) shows that drug-resistant cells initially generate ceramide in response to SDZ PSC 833, but this ceramide is converted to glucosylceramide. Studies with fumonisin B1 (73,81,137) and analyses of sphingomyelin decay indicate that SDZ PSC 833 activates de novo synthesis of ceramide in cancer cells. Examination of intracellular ceramide metabolites showed that doxorubicin-resistant MCF-7-AdrR breast cancer cells converted ceramide to glucosylceramide, whereas drug-sensitive MCF-7 cells contained only free ceramide and no detectable glucosylceramide (126).
1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP), 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP), and 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) are structural analogues of the natural sphingolipid substrate of GCS and are potent competitive enzyme inhibitors (140). PPMP effectively inhibits glucosylceramide synthesis (50% inhibitory concentrations = 0.9 µM) in MCF-7-AdrR cells (80). A PPMP concentration that maximally inhibits glucosylceramide synthesis has no effect on cell viability but does sensitize cells to doxorubicin (80). Nicholson et al. (141) showed preferential killing of drug-resistant cell lines by PPMP and its analogue PPPP. Spinedi et al. (142) showed that PDMP suppressed glucosylceramide synthesis and markedly potentiated the apoptotic effect of C6-ceramide in CHP-100 neuroepithelioma cells. The authors concluded that activation of glucosylceramide synthesis is a cellular mechanism for escape from ceramide-induced apoptosis.
The imino sugars N-butyldeoxynojirimycin and N-butyldeoxygalactonojirimycin also inhibit GCS (143,144) and are currently in clinical trials for treatment of Gaucher's disease (a glycosphingolipid lysosomal storage disease). The ability to block ceramide glycosylation makes the imino sugars promising therapeutic agents for the treatment strategy shown in Fig. 1.
Studies indicate that the coadministration of ceramide metabolism modulators enhances levels of ceramide. Investigators have shown that cytotoxicity of the novel synthetic retinoid 4-HPR can be enhanced by adding modulators of ceramide metabolism (145). Exposure of CHLA90 cells to 4-HPR produced a fivefold increase in ceramide levels, a fourfold increase in glucosylceramide levels, and a 2.5 order of magnitude increase in cell killing (83). When PPMP was added, inhibition of GCS completely prevented the increase in glucosylceramide, yielded a sevenfold increase in ceramide levels, and produced a synergistic multiorder of magnitude increase in cytotoxicity (145). Adding tamoxifen to treatment with SDZ PSC 833 in MCF-7/AdrR breast cancer cells increasingly inhibits the metabolism of ceramide and further diminishes cell survival. When treatment with tamoxifen is combined with doxorubicin, ceramide levels increase fivefold to 26-fold and cell survival drops to zero (81). It appears that drug combinations eliciting the greatest ceramide increase may be the most cytotoxic.
A number of pathways affecting the metabolic fate of ceramide are activated in response to various chemosensitizing agents. Nevertheless, in some cases, the mechanisms by which ceramide metabolism is affected by these agents is not completely clear. In some cells treated with PPMP, ceramide increases (146) as a result of blocking glycosylation. The mode by which agents, such as tamoxifen, cyclosporine A, mifepristone, and verapamil, elevate ceramide is poorly understood. Although these drugs block the formation of glucosylceramide from ceramide (79,80,126,130,131), direct interaction with GCS has not been demonstrated. These agents, therefore, cannot be considered to be glycosylation inhibitors; instead they might induce apoptosis by direct binding to target proteins of ceramide. However, work with 4-HPR suggests direct targeting of the enzymes of de novo ceramide synthesis (83,145). Pre-exposure of intact neuroblastoma cells to 4-HPR elicits time- and dose-dependent increases in serine palmitoyltransferase and ceramide synthase, as measured in in vitro assays with microsomes (our unpublished data).
The role of GCS in regulating cellular response to chemotherapy has also been demonstrated by introducing GCS antisense complementary DNA (cDNA) into doxorubicin-resistant cancer cells (Fig. 4). Transfecting drug-resistant MCF-7/AdrR cells with GCS antisense cDNA decreases cellular glycosylation, effectively reversing drug resistance (147,148). Reverse transcription-coupled polymerase chain reaction, western blot, and in vitro assays showed that MCF-7-AdrR/asGCS, the cell line generated, has decreased GCS mRNA, GCS protein, and GCS enzymatic activity and is 28-fold more sensitive to doxorubicin than the parent MCF-7-AdrR cell line. Exposure to doxorubicin causes both time- and dose-dependent increases in ceramide levels, caspase-3 activity, and cell death in MCF-7-AdrR/asGCS cells transfected with GCS antisense when compared with MCF-7/AdrR parent cells. These findings demonstrate that transfection of GCS antisense restores sensitivity to anthracyclines and resumption of ceramide/caspase apoptotic signaling. A reverse scenario also has been demonstrated by transfecting drug-sensitive MCF-7 breast cancer cells with GCS sense cDNA (Fig. 4
), conferring chemotherapy resistance (21,22).
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CONCLUSIONS |
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NOTES |
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Supported in part by Public Health Service grant CA77632 (to M. C. Cabot) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by grant 737V20037 from the California Cancer Research Program; by the Strauss Foundation, Sandra Krause, Trustee; by the Streisand Foundation; by the Fashion Footwear Association of New York Shoes on SaleTM; by the Associates for Breast and Prostate Cancer Studies, Los Angeles, CA; by the John Wayne Cancer Institute Auxiliary; and by the Leslie & Susan Gonda (Goldschmied) Foundation.
We thank Ms. Weiling Chen, Dhory Baghallian, and Gwen Berry for their assistance.
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Manuscript received February 10, 2000; revised November 30, 2000; accepted December 29, 2000.
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