Targeting Ceramide Metabolism--a Strategy for Overcoming Drug Resistance

Senchenkov, Alex; Litvak, David A.; Cabot, Myles C.

doi:10.1093/jnci/93.5.347

Cited by 297 publications

(277 citation statements)

References 110 publications

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“…Treatment of cancer cells with radiation and chemotherapeutics such as vincristine, daunorubicin, gemcitabine, and etoposide result in ceramide accumulation in the cells as a secondary effect of these therapeutics [187]. Decreased ceramide levels result in the development of drug resistance in cancer cells [188]. In vitro studies indicated that treatment of cancer cells with ceramide triggers the release of cytochrome-c from the mitochondria [189].…”

Section: Bioactive Sphingolipids In Apoptotic Pathwaysmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

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Section: Bioactive Sphingolipids In Apoptotic Pathwaysmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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“…25,26 The mechanism behind this interaction is not completely understood, but it is likely that mitochondrial cytochrome c release is important to the induction of apoptosis by 4HPR and chemotherapy. 21,27,28 Previous work has shown that TRAIL induces direct caspase activation and that, in some cells, TRAIL also induces mitochondrial cytochrome c release and caspase activation. 29 Thus, we investigated if 4HPR could enhance TRAIL-mediated apoptosis in ovarian cancer cells, which are resistant to TRAIL-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

et al. 2004

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The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer.

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“…One strategy to treat MRD is to restore sensitivity to chemotherapeutic drugs. It has been recently reported, that a MDR phenotype is often associated with aberrant ceramide metabolism [77]. In this context, TNF-α-resistant MCF7 breast cancer cells have been characterized by the inability of their neutral or acidic sphingomyelinases to generate ceramide [78].…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated in breast and in prostate cancer, that treatment of MDR cancer cells with either inhibitors of GCS or inhibitors of S1P restored sensitivity to chemotherapeutic agents [71,77,79].…”

Section: Discussionmentioning

confidence: 99%