Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells
Abstract
:Simple Summary
Abstract
1. Introduction
2. The Ceramide Biosynthesis Pathway
3. Ceramidase
3.1. Acid Ceramidase
3.2. Role of AC in Pathological Conditions
3.2.1. Prostate Cancer (PC)
3.2.2. Head- and Neck Cancer (HNC)
3.2.3. Melanoma
3.2.4. Myeloid Leukemia
3.2.5. Non-Small Cell Lung Cancer (NSCLC)
3.2.6. Breast Cancer
3.2.7. Ovarian Cancer (OC)
3.2.8. Hepatobiliary Cancers
3.2.9. Colon Cancer
4. Sphingosine Kinase
5. Sphingomyelin Synthase
Biological Significance of Sphingomyelin Synthase
6. 3-Ketosphinganine Reductase
7. Dihydroceramide Desaturase
7.1. Role of Dihydroceramides in Various Diseases
7.1.1. DhCer in Brain Diseases
7.1.2. DhCer in Cardiovascular Disease
7.1.3. DhCer in Cancer Therapy
8. (Dihydro)ceramide Synthase
9. Ceramide Synthases
9.1. Ceramide Synthase 1
9.2. Ceramide Synthase 2
9.3. Ceramide Synthase 3
9.4. Ceramide Synthase 4
9.5. Ceramide Synthase 5
9.6. Ceramide Synthase 6
10. Natural Product Inhibitors and Their Analogs
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
SL | Sphingolipid |
S1P | Sphingosine-1-phosphate |
CDases | Ceramidases |
AC | Acid ceramidase |
AML | Acute myeloid leukemia |
HNC | Head- and Neck Cancer |
SMS | Sphingomyelin synthase |
DES | Dihydroceramide desaturase |
DHSph | Dihydrosphingosine |
CerS | Ceramide synthase |
GMZ | Gemcitabine |
FD | Farber disease |
siRNA | Small interfering RNA |
PPC-1 | Primary prostatic carcinoma cell line |
NOE | N-oleoylethanolamine |
DTIC | Dacarbazine |
IRF8 | IFN regulatory factor 8 |
NSCLC | Non-Small Cell Lung Cancer |
DCIS | Ductal carcinoma in situ |
HER2 | Human Epidermal Growth Factor Receptor 2 |
OC | Ovarian cancer |
dCK | Deoxycytidine kinase |
CDA | Cytidine deaminase |
CERT | Ceramide transfer protein |
KSR | 3-Ketosphinganine reductase |
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Enzyme | Inhibitors | Mechanism of Action and Binding Characteristics | Ref # |
---|---|---|---|
Acid Ceramidase | (Carmoflur) | Carmoflur decreases the growth of glioblastoma cell lines and cells isolated from glioblastoma-patient-derived xenografts. It covalently binds to the active site of ASAH1 to inhibit its function, resulting in increased C14:0, C16:0, and C18:0 ceramide. | [185] |
Acid Ceramidase | (Fenretinide) | Fenretinide treatment results in a cellular ceramide increase in tumor cells. The MOA involves ROS accumulation, cytochrome C release from mitochondrial membrane resulting in mitochondrial membrane depolarization, and cell apoptosis. | [186] |
Sphingomyelin synthase | (jaspine B) | In vitro studies in cancer cells demonstrated that mitochondrial membrane bound cytochrome C release, resulting in apoptosis. | [187] |
Sphingosine Kinase | (ABC294640) | Sphingosine Kinase II specific competitive inhibitor. SphKII binding models suggest ABC294640 binding in a J-channel of the active site. | [188] |
Sphingosine Kinase II | (SG-12) | SG-12 is a synthetic analogue of sphingosine that acts as an SKII inhibitor. It induces apoptosis via phosphorylation by SKII. | [72] |
Sphingosine Kinase II | (FTY720-OMe) | (R)-FTY720-OMe helps block DNA synthesis and actin rearrangement induced by sphingosine 1-phosphate (S1P) in MCF-7 breast cancer cells. It can also reduce sphingosine kinase 2 (SK2) expression and prevent DNA synthesis in HEK 293 cells. | [73] |
Sphingosine Kinase II | (K145) | Apoptotic effects in U937 cells, possibly through inhibition of the phosphorylation of downstream RK and Akt signaling pathways. | [74] |
Sphingosine Kinase I | (PF—543) | Despite being SK1 selective, PF-543 demonstrates poor anticancer activity in several cancer cells. | [189] |
Dihydroceramide desaturase | (Curcumin) | In a model of lipid trafficking impairment in C6 glial cells, curcumin stimulated ceramide synthesis by increasing the intracellular concentration of ceramide-dihydroceramide. | [190] |
Dihydroceramide desaturase | (XM462) | Inhibition studies in rat liver microsomes proved XM462 as mixed type inhibitor by a dose dependent inhibition of DES1. | [191] |
Dihydroceramide desaturase | (GT11) | A Cyclopropene ring mimics the ceramide double bond, the natural 2S,3R stereochemistry, a free hydroxyl group, amide, and alkyl chains. | [191] |
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Afrin, F.; Mateen, S.; Oman, J.; Lai, J.C.K.; Barrott, J.J.; Pashikanti, S. Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells. Cancers 2023, 15, 4645. https://doi.org/10.3390/cancers15184645
Afrin F, Mateen S, Oman J, Lai JCK, Barrott JJ, Pashikanti S. Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells. Cancers. 2023; 15(18):4645. https://doi.org/10.3390/cancers15184645
Chicago/Turabian StyleAfrin, Farjana, Sameena Mateen, Jordan Oman, James C. K. Lai, Jared J. Barrott, and Srinath Pashikanti. 2023. "Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells" Cancers 15, no. 18: 4645. https://doi.org/10.3390/cancers15184645
APA StyleAfrin, F., Mateen, S., Oman, J., Lai, J. C. K., Barrott, J. J., & Pashikanti, S. (2023). Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells. Cancers, 15(18), 4645. https://doi.org/10.3390/cancers15184645