Inhibition of acid ceramidase by a 2‐substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N‐(4‐hydroxyphenyl) retinamide

Gouazé-Andersson, Valérie; Flowers, Margaret; Karimi, Ramin; Fabriás, Gemma; Delgado, Antonio; Casas, Josefina; Cabot, Myles C.

doi:10.1002/pros.21321

Cited by 46 publications

(38 citation statements)

References 43 publications

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“…A promising strategy to enhance intracellular ceramide levels involves targeting proteins that regulate ceramide levels. Examples include the acid ceramidase inhibitor DM102 in prostate and breast cancer cell lines (29), tamoxifen (which acts as a potent inhibitor of ceramide glycosylation) in triple-negative breast cancer (24), and, finally, safingol, an inhibitor of sphingosine kinase with efficacies in colon, breast, ovarian, and cervical cancer models currently enrolled in phase I clinical trials (30,31). Here, we have identified the Bcl-2 family protein Bcl2L13 as a first-in-class inhibitor of CerS activity in cancer, particularly in GBM.…”

Section: Discussionmentioning

confidence: 99%

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

Jensen¹,

Calvert²,

Volpert

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Molecular mechanisms of therapy (apoptosis) resistance in cancer are poorly understood. Here, we have identified Bcl2-like 13 (Bcl2L13) as a ceramide synthase inhibitor that is overexpressed in glioblastoma (GBM) and other malignancies. Bcl2L13 inhibits therapy-induced apoptosis and promotes GBM tumor growth in vivo. Mechanistically, Bcl2L13 binds to proapoptotic ceramide synthases 2 (CerS2) and 6 (CerS6) and blocks CerS2/6 complex formation and activity. Correspondingly, CerS2/6 activity and Bcl2L13 abundance are inversely correlated in GBM tumors, thereby providing a molecular explanation for the low levels of proapoptotic ceramide species in high-grade gliomas, which are associated with poor survival. To our knowledge, this work provides the first evidence of direct regulation of CerS activity by a Bcl-2 family member and establishes the Bcl2L13–CerS axis as a target for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

Jensen¹,

Calvert²,

Volpert

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…These experiments showed that inhibition of enzymes responsible for the production of apoptotic sphingolipid species (or in some cases overexpression of opposing enzymes) abrogates the cytotoxicity of the drug, and conversely overexpression of the same enzymes correlated with increased chemotherapeutic sensitivity suggesting that certain sphingolipid species are important for cytotoxicity of the drug [219][220][221]. Some other studies have also shown that therapeutic efficacy of cancer drugs can be significantly enhanced in combination with growth-suppressive sphingolipids such as ceramides and sphingosine [222][223][224]. Therefore, manipulation of sphingolipid metabolism comes forward as a good intervention approach for novel therapies [225].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 96%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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“…While the characterization of aberrant, cancer-associated gene expression in tissues obtained for diagnosis versus noncancerous tissues is a prominent arena of research (39), the response of tumors to therapy also represents a critical avenue of investigation (22). Work by this group and others has demonstrated that the ceramide-metabolizing enzyme, acid ceramidase (AC), can play an important role in resistance to anticancer therapies (40)(41)(42)(43)(44)(45)(46)(47), including IR (26,36,48,49). In this report, we evaluated transcriptional activation of AC in PCa cells treated with radiation.…”

Section: Introductionmentioning

confidence: 99%

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

et al. 2013

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Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

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Inhibition of acid ceramidase by a 2‐substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N‐(4‐hydroxyphenyl) retinamide

Cited by 46 publications

References 43 publications

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

Bcl2L13 is a ceramide synthase inhibitor in glioblastoma

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

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