270:
654:. However, an initial increase in phosphorylated mTOR is also observed, which eventually reduces after several hours. The mTOR pathway normally inhibits autophagy, as is induced by heightened glucose uptake. Therefore, decreasing glucose levels should suppress the mTOR pathway, allowing for autophagy. While autophagy is indeed observed following exposure of safingol, it is intriguing that mTOR is activated initially. Modulations in
397:
35:
547:. Increased autophagic activity has been associated with increased cellular death, although it is unclear if there is any causative relationship between the two. Because autophagy normally plays a pro-survival role by impeding apoptosis, it is curious that it may play a role in cell death following safingol exposure.
726:
Schwartz GK, Haimovitz-Friedman A, Dhupar SK, Ehleiter D, Maslak P, Lai L, Loganzo F Jr, Kelsen DP, Fuks Z, Albino AP (1995). "Potentiation of apoptosis by treatment with the protein kinase C-specific inhibitor safingol in mitomycin C-treated gastric cancer cells".
639:
is that high concentrations result in ROS-related molecular and cellular damage that is beyond repair. Therefore, autophagy does not directly contribute to death, but is rather a failed attempt to preserve cell viability. However, not only does this
594:, leading to the generation of ROS that are both time and concentration-dependent. Together, the inhibitory signaling effects (particularly of PKCε and PI3k) and the presence of ROS synergize to induce autophagy.
597:
Following autophagic activity, cell death is eventually induced by an as of yet unknown mechanism. Missing from this cellular death are any signs of apoptotic induction such as characteristic changes to
986:
410:
882:"Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C"
979:
531:
The underlying mechanism by which safingol induces cell death is poorly understood. It is believed to exert a variety of inhibitory effects, resulting in a series of
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319:
681:. This ability further contributes to its anticancer potential. It can also affect the balance of other endogenous sphingolipids, particularly
163:
644:
warrants further testing, but safingol has demonstrated unusual regulatory effects on other pathways capable of regulating autophagy.
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1026:
926:"Safingol (L-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway"
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417:
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924:
Coward J, Ambrosini G, Musi E, Truman JP, Haimovitz-Friedman A, Allegood JC, Wang E, Merrill AH Jr, Schwartz GK (2009).
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InChI=1S/C18H39NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-18(21)17(19)16-20/h17-18,20-21H,2-16,19H2,1H3/t17-,18-/m0/s1
606:
303:
InChI=1/C18H39NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-18(21)17(19)16-20/h17-18,20-21H,2-16,19H2,1H3/t17-,18-/m0/s1
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from mitochondria are also thought to play a role in safingol-induced cellular death by regulating autophagy.
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491:. However, preclinical and clinical studies have shown that combining safingol with conventional
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has not been observed, suggesting that this necrosis is accidental in nature and not programmed.
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831:"A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors"
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481:. The administration of safingol alone has not been shown to exert a significant effect on
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777:"The role of reactive oxygen species and autophagy in safingol-induced cell death"
677:(S1P), an important mediator of cancer cell growth, proliferation, invasion, and
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Dickson MA, Carvajal RD, Merrill AH Jr, Gonen M, Cane LM, Schwartz GK (2011).
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586:. Furthermore, safingol, like other sphingolipids, has been found to inhibit
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cleavage. Instead, several hallmarks of necrosis are observed, such as
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Except where otherwise noted, data are given for materials in their
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can dramatically potentiate their antitumor effects. In
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family, inhibiting the activation of such enzymes as
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716:. Retrieved 21 March 2024 from Millipore Sigma.
880:Sachs CW, Safa AR, Harrison SD, Fine RL (1995).
515:, it was found to be safe to co-administer with
207:
137:
130:
980:
647:As expected, a decrease in glucose heightens
578:(PI3k), which is a critical component of the
8:
1376:
1325:
1022:
987:
973:
965:
673:(SphK), which catalyzes the production of
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26:
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897:
856:
846:
802:
792:
669:Safingol is also a putative inhibitor of
635:One potential explanation for safingol’s
234:
227:
1108:Tooltip Sphingosine-1-phosphate receptor
775:Ling LU, Tan KB, Lin H, Chiu GN (2011).
729:Journal of the National Cancer Institute
698:
519:, but caused reversible dose-dependent
324:
289:
264:
1442:3-Ketosphinganine (dehydrosphingosine)
1032:Tooltip Lysophosphatidic acid receptor
469:, safingol has demonstrated promising
1335:Tooltip Serine C-palmitoyltransferase
1164:Dihydro-S1P (sphinganine 1-phosphate)
624:, and the depletion of intracellular
613:-independent cell death, the loss of
550:Safingol competitively competes with
296:Key: OTKJDMGTUTTYMP-ROUUACIJSA-N
7:
306:Key: OTKJDMGTUTTYMP-ROUUACIJBJ
198:
473:potential as a modulator of multi-
25:
1447:Dihydrosphingosine (sphinganine)
395:
360:
354:
109:-1,3-Dihydroxy-2-aminooctadecane
33:
886:Journal of Biological Chemistry
391:(at 25 °C , 100 kPa).
628:. However, the involvement of
363:
348:
81:)-2-Amino-1,3-octadecanediol;
1:
1477:Receptor/signaling modulators
848:10.1158/1078-0432.CCR-10-2323
105:-2-Amino-1,3-octadecanediol;
574:. Safingol can also inhibit
539:cell death brought about by
60:)-2-Aminooctadecane-1,3-diol
617:integrity, the collapse of
1518:
1381:Tooltip Sphingosine kinase
535:that result in accidental
1470:
576:phosphoinositide 3-kinase
385:
335:
315:
280:
114:
66:
46:
41:
32:
899:10.1074/jbc.270.44.26639
835:Clinical Cancer Research
781:Cell Death & Disease
590:uptake. This results in
741:10.1093/jnci/87.18.1394
675:sphingosine 1-phosphate
541:reactive oxygen species
513:phase I clinical trials
327:OC(N)(O)CCCCCCCCCCCCCCC
73:-Dihydrosphingosine; (2
543:(ROS) and mediated by
794:10.1038/cddis.2011.12
477:and as an inducer of
97:-Dihydrosphingosine;
1174:Fingolimod phosphate
943:10.4161/auto.5.2.736
671:sphingosine kinase 1
48:Preferred IUPAC name
892:(44): 26639–26648.
710:-Dihydrosphingosine
461:and is a colorless
381: g·mol
29:
622:membrane potential
556:regulatory domains
552:phorbol dibutyrate
418:Infobox references
27:
1484:
1483:
1407:
1406:
1322:
1307:
1306:
1019:
735:(18): 1394–1399.
584:MAPK/ERK pathways
447:molecular formula
426:Chemical compound
424:
423:
249:CompTox Dashboard
164:Interactive image
100:
92:
84:
16:(Redirected from
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996:Lysophospholipid
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841:(8): 2484–2492.
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815:. Art. No. e129.
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592:oxidative stress
560:protein kinase C
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1452:Dihydroceramide
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1048:1-Palmitoyl-LPA
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615:plasma membrane
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664:endonuclease G
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89:-Sphinganine;
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1432:Palmitoyl-CoA
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445:. It has the
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266:DTXSID9045768
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1393:
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1261:Antagonists:
1260:
1115:
1070:Antagonists:
1069:
1043:1-Oleoyl-LPA
1039:
961:
933:
929:
889:
885:
875:
838:
834:
784:
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732:
728:
721:
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679:angiogenesis
668:
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637:cytotoxicity
634:
596:
549:
530:
493:chemotherapy
434:sphingolipid
429:
428:
115:Identifiers
106:
102:
94:
86:
78:
74:
70:
67:Other names
57:
53:
1462:Sphingosine
1419:Precursors:
1129:Ceralifimod
1078:H2L-5765834
1073:H2L-5186303
509:mitomycin C
501:vinblastine
497:fenretinide
467:Medicinally
336:Properties
239: (HCl)
142: (HCl)
139:139755-79-6
18:Sphinganine
1491:Categories
1353:Ceramidase
1319:inhibitors
1184:Mocravimod
1169:Fingolimod
1119:Amiselimod
1053:GRI-977143
1002:modulators
693:References
642:hypothesis
603:morphology
505:irinotecan
471:anticancer
432:is a lyso-
374:Molar mass
236:30MA50WJ4N
229:OWA98U788S
175:ChemSpider
151:3D model (
132:15639-50-6
122:CAS Number
1474:See also:
1361:Ceranib 1
1299:Etrasimod
1296:Unsorted:
1284:VPC-23019
1269:CYM-50358
1239:TC-G 1006
1224:Siponimod
1199:Ponesimod
1194:Phyto-S1P
1159:CYM-50308
1154:CYM-50260
1124:Cenerimod
1116:Agonists:
1093:VPC-32183
1088:TC-LPA5 4
1040:Agonists:
999:signaling
930:Autophagy
545:autophagy
527:Mechanism
517:cisplatin
443:inhibitor
28:Safingol
1457:Ceramide
1394:Safingol
1343:Myriocin
1279:TY-52156
1244:TC-SP 14
1219:SEW-2871
1214:RPC-1063
1189:Ozanimod
1149:CYM 5541
1144:CYM-5520
1139:CYM-5442
1083:Ki-16425
1010:Receptor
952:19098447
867:21257722
813:21390063
683:ceramide
537:necrotic
533:cascades
479:necrosis
430:Safingol
1389:N,N-DMS
1274:JTE-013
1264:CS-0777
1254:XAX-162
1179:KRP-203
1134:CS-2100
1016:ligands
908:7592889
858:3078945
804:3101809
749:7658500
611:caspase
600:nuclear
588:glucose
558:of the
437:protein
411:what is
409: (
379:301.515
209:3058739
196:PubChem
184:2319840
1497:Amines
1437:Serine
1412:Others
1399:SKI II
1313:Enzyme
1209:RP-002
1204:RP-001
950:
906:
865:
855:
811:
801:
747:
662:, and
660:Bcl-xL
570:, and
564:PKCβ-I
489:growth
440:kinase
406:verify
403:
320:SMILES
42:Names
1502:Diols
1289:W-146
1249:W-061
787:(3).
708:threo
656:Bcl-2
630:RIPK1
483:tumor
463:solid
285:InChI
153:JSmol
107:threo
103:threo
95:threo
87:threo
85:-(−)-
71:threo
1429:S1P:
1422:LPA:
1377:SphK
1104:S1PR
1063:OMPT
1028:LPAR
948:PMID
904:PMID
863:PMID
809:PMID
745:PMID
685:and
649:AMPK
607:PARP
605:and
582:and
580:mTOR
572:PKCε
568:PKCδ
507:and
486:cell
220:UNII
69:(−)-
1425:LPC
1366:OEA
1331:SPT
1234:SPC
1229:S1P
1058:LPA
938:doi
894:doi
890:270
853:PMC
843:doi
799:PMC
789:doi
737:doi
712:at
706:DL-
626:ATP
554:at
523:.
254:EPA
199:CID
1493::
1427:;
946:.
932:.
928:.
916:^
902:.
888:.
884:.
861:.
851:.
839:17
837:.
833:.
821:^
807:.
797:.
783:.
779:.
757:^
743:.
733:87
731:.
658:,
566:,
503:,
499:,
465:.
457:NO
455:39
451:18
358:39
352:18
77:,3
56:,3
52:(2
1321:)
1317:(
1018:)
1014:(
988:e
981:t
974:v
954:.
940::
934:5
910:.
896::
869:.
845::
791::
785:2
751:.
739::
459:2
453:H
449:C
401:N
367:2
364:O
361:N
355:H
349:C
256:)
252:(
155:)
101:-
99:L
93:-
91:L
83:L
79:S
75:S
58:S
54:S
20:)
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