|
|
| navitoclax |
|
| CHEBI:131174 |
|
| A N-sulfonylcarboxamide resulting from the formal condensation of the carboxy group of 4-{4-[(4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro[biphenyl]-2-yl)methyl]piperazin-1-yl}benzoic acid with the amino group of 4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide. It is a BH3-mimetic drug which targets the anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, and induces apoptosis in cancer cells. Currently under clinical investigation as treatment for solid tumors and hematologic malignancies. |
|
This entity has been manually annotated by the ChEBI Team.
|
|
|
CHEBI:94128
|
|
| ChemicalBook:CB21872884, eMolecules:27515371, Selleckchem:ABT-263, ZINC000150338726 |
|
|
Molfile
XML
SDF
|
|
|
more structures >>
|
|
call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__540160592691874__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__540160592691874__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:94128","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__540160592691874__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"540160592691874","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__540160592691874__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol 1XJ - Ideal conformer RDKit 3D starting HoverWatcher_5 Time for openFile(1XJ - Ideal conformer RDKit 3D 120126 0 0 0 0 0 0 0 0999 V2000 8.2350 1.6590 -1.6170 C 0 0 0 0 0 0 0 0 0 0 0 0 10.3390 0.7010 -0.9220 C 0 0 0 0 0 0 0 0 0 0 0 0 1.2970 -3.0490 1.6400 C 0 0 0 0 0 0 0 0 0 0 0 0 1.8360 -3.1780 -0.7160 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6060 -2.7270 1.9180 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.4670 -0.7600 -1.7760 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.6950 -1.8550 -2.1090 C 0 0 0 0 0 0 0 0 0 0 0 0 10.5300 0.2110 -2.1970 C 0 0 0 0 0 0 0 0 0 0 0 0 9.1870 1.4310 -0.6230 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.9890 -0.6430 -0.4940 C 0 0 0 0 0 0 0 0 0 0 0 0 -10.0860 2.0570 -0.3480 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4410 -2.8350 -1.1670 C 0 0 0 0 0 0 0 0 0 0 0 0 9.5840 0.4450 -3.1800 C 0 0 0 0 0 0 0 0 0 0 0 0 8.6920 1.1080 1.6960 C 0 0 0 0 0 0 0 0 0 0 0 0 9.1040 3.4400 0.9520 C 0 0 0 0 0 0 0 0 0 0 0 0 -12.2610 3.6360 0.3080 C 0 0 0 0 0 0 0 0 0 0 0 0 -11.0050 4.2040 0.1970 C 0 0 0 0 0 0 0 0 0 0 0 0 -12.4330 2.2810 0.0910 C 0 0 0 0 0 0 0 0 0 0 0 0 3.1430 -2.8550 -0.4310 C 0 0 0 0 0 0 0 0 0 0 0 0 -9.9170 3.4190 -0.1300 C 0 0 0 0 0 0 0 0 0 0 0 0 -11.3490 1.4900 -0.2360 C 0 0 0 0 0 0 0 0 0 0 0 0 8.4370 1.1630 -2.8880 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.9590 -2.7230 0.1100 C 0 0 0 0 0 0 0 0 0 0 0 0 0.9010 -3.2770 0.3190 C 0 0 0 0 0 0 0 0 0 0 0 0 3.5350 -2.6280 0.8860 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.7370 -1.6330 0.4470 C 0 0 0 0 0 0 0 0 0 0 0 0 8.9770 1.9590 0.7410 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.5010 -3.6230 0.0170 C 0 0 0 0 0 0 0 0 0 0 0 0 8.4450 1.5030 3.1230 C 0 0 0 0 0 0 0 0 0 0 0 0 8.4520 3.8410 2.2770 C 0 0 0 0 0 0 0 0 0 0 0 0 4.9390 -1.0310 1.9030 C 0 0 0 0 0 0 0 0 0 0 0 0 5.6620 -2.2510 -0.0580 C 0 0 0 0 0 0 0 0 0 0 0 0 6.3990 -0.7480 2.2660 C 0 0 0 0 0 0 0 0 0 0 0 0 7.1220 -1.9690 0.3050 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.7040 3.8110 -2.6630 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.2040 2.0820 -1.8760 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.5540 4.8190 -2.6020 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.0690 3.1080 -1.8230 C 0 0 0 0 0 0 0 0 0 0 0 0 8.9790 2.9130 3.3790 C 0 0 0 0 0 0 0 0 0 0 0 0 10.5090 2.8960 3.3530 C 0 0 0 0 0 0 0 0 0 0 0 0 8.4940 3.4080 4.7430 C 0 0 0 0 0 0 0 0 0 0 0 0 8.6010 -0.3540 1.3390 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.8720 2.5080 -1.1600 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5990 1.8070 -1.6390 C 0 0 0 0 0 0 0 0 0 0 0 0 -7.3280 2.2370 -0.7890 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.0310 1.5090 -1.1470 C 0 0 2 0 0 0 0 0 0 0 0 0 -4.5700 -0.0330 2.7720 C 0 0 0 0 0 0 0 0 0 0 0 0 4.8560 -2.3020 1.1700 N 0 0 0 0 0 0 0 0 0 0 0 0 -5.7650 0.4670 -0.1520 N 0 0 0 0 0 0 0 0 0 0 0 0 -0.8810 -3.8430 -1.2570 N 0 0 0 0 0 0 0 0 0 0 0 0 7.2050 -0.6980 1.0380 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.4870 2.7660 -1.6520 N 0 0 0 0 0 0 0 0 0 0 0 0 -1.3130 -3.7100 0.9170 O 0 0 0 0 0 0 0 0 0 0 0 0 -6.7780 -1.2300 1.8720 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.9620 -2.6720 2.7340 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.8150 -5.2690 -0.6950 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.5400 -4.3650 -3.0080 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.3130 4.1330 -2.7910 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.8640 1.0890 1.9890 F 0 0 0 0 0 0 0 0 0 0 0 0 -3.1870 -0.2430 2.7850 F 0 0 0 0 0 0 0 0 0 0 0 0 -5.0220 0.1790 4.0790 F 0 0 0 0 0 0 0 0 0 0 0 0 -8.7010 1.0530 -0.7730 S 0 0 0 0 0 0 0 0 0 0 0 0 -5.3960 -1.4900 2.0750 S 0 0 0 0 0 6 0 0 0 0 0 0 -2.4550 -4.2320 -1.5960 S 0 0 0 0 0 6 0 0 0 0 0 0 9.8310 -0.1760 -4.7830 Cl 0 0 0 0 0 0 0 0 0 0 0 0 7.3400 2.2190 -1.3900 H 0 0 0 0 0 0 0 0 0 0 0 0 11.0770 0.5180 -0.1550 H 0 0 0 0 0 0 0 0 0 0 0 0 0.5780 -3.1290 2.4410 H 0 0 0 0 0 0 0 0 0 0 0 0 1.5330 -3.3540 -1.7370 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9130 -2.5500 2.9380 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.6610 0.0080 -2.5110 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2890 -1.9460 -3.1060 H 0 0 0 0 0 0 0 0 0 0 0 0 11.4190 -0.3570 -2.4280 H 0 0 0 0 0 0 0 0 0 0 0 0 10.1590 3.7140 0.9710 H 0 0 0 0 0 0 0 0 0 0 0 0 8.6090 3.9650 0.1350 H 0 0 0 0 0 0 0 0 0 0 0 0 -13.1100 4.2520 0.5650 H 0 0 0 0 0 0 0 0 0 0 0 0 -10.8750 5.2630 0.3670 H 0 0 0 0 0 0 0 0 0 0 0 0 -13.4150 1.8410 0.1790 H 0 0 0 0 0 0 0 0 0 0 0 0 3.8660 -2.7770 -1.2300 H 0 0 0 0 0 0 0 0 0 0 0 0 -8.9360 3.8630 -0.2150 H 0 0 0 0 0 0 0 0 0 0 0 0 -11.4840 0.4320 -0.4050 H 0 0 0 0 0 0 0 0 0 0 0 0 7.6990 1.3360 -3.6580 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7590 -3.4910 0.8420 H 0 0 0 0 0 0 0 0 0 0 0 0 7.3740 1.4800 3.3230 H 0 0 0 0 0 0 0 0 0 0 0 0 8.9490 0.7990 3.7850 H 0 0 0 0 0 0 0 0 0 0 0 0 8.7090 4.8740 2.5140 H 0 0 0 0 0 0 0 0 0 0 0 0 7.3700 3.7420 2.1980 H 0 0 0 0 0 0 0 0 0 0 0 0 4.3440 -1.0980 2.8150 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5570 -0.2240 1.2780 H 0 0 0 0 0 0 0 0 0 0 0 0 5.2880 -1.4590 -0.7060 H 0 0 0 0 0 0 0 0 0 0 0 0 5.5950 -3.2080 -0.5760 H 0 0 0 0 0 0 0 0 0 0 0 0 6.4660 0.2080 2.7850 H 0 0 0 0 0 0 0 0 0 0 0 0 6.7720 -1.5410 2.9140 H 0 0 0 0 0 0 0 0 0 0 0 0 7.5040 -2.7760 0.9310 H 0 0 0 0 0 0 0 0 0 0 0 0 7.7170 -1.9020 -0.6060 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.6460 4.3210 -2.4630 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.7380 3.3580 -3.6540 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2140 1.6010 -2.8540 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.0530 1.3310 -1.1020 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6800 5.5640 -3.3880 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5530 5.3120 -1.6300 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0250 3.5510 -0.8280 H 0 0 0 0 0 0 0 0 0 0 0 0 0.8770 2.6160 -2.0450 H 0 0 0 0 0 0 0 0 0 0 0 0 10.8520 2.5510 2.3780 H 0 0 0 0 0 0 0 0 0 0 0 0 10.8870 3.9020 3.5360 H 0 0 0 0 0 0 0 0 0 0 0 0 10.8780 2.2230 4.1270 H 0 0 0 0 0 0 0 0 0 0 0 0 8.8550 2.7370 5.5220 H 0 0 0 0 0 0 0 0 0 0 0 0 8.8760 4.4120 4.9230 H 0 0 0 0 0 0 0 0 0 0 0 0 7.4040 3.4250 4.7560 H 0 0 0 0 0 0 0 0 0 0 0 0 9.2210 -0.5530 0.4650 H 0 0 0 0 0 0 0 0 0 0 0 0 8.9510 -0.9550 2.1780 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7160 2.8970 -0.1540 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.1090 3.3310 -1.8350 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3620 0.9840 -0.9650 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7550 1.4180 -2.6450 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.2290 2.6920 0.1970 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.5250 3.0130 -1.5290 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.1300 1.0540 -2.1320 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.1290 0.5470 0.7430 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.2330 -3.7740 -1.9760 H 0 0 0 0 0 0 0 0 0 0 0 0 57 64 2 0 53 28 2 0 64 56 2 0 64 50 1 0 64 12 1 0 7 6 2 0 7 12 1 0 28 50 1 0 28 24 1 0 6 10 1 0 12 23 2 0 3 24 2 0 3 5 1 0 24 4 1 0 5 25 2 0 4 19 2 0 36 52 1 0 36 38 1 0 44 52 1 0 44 43 1 0 46 45 1 0 46 43 1 0 46 49 1 0 10 26 2 0 10 49 1 0 45 62 1 0 23 26 1 0 32 48 1 0 32 34 1 0 25 19 1 0 25 48 1 0 52 35 1 0 38 58 1 0 26 63 1 0 20 17 1 0 20 11 2 0 17 16 2 0 48 31 1 0 60 47 1 0 34 51 1 0 61 47 1 0 31 33 1 0 51 33 1 0 51 42 1 0 58 37 1 0 35 37 1 0 62 11 1 0 47 63 1 0 47 59 1 0 11 21 1 0 40 39 1 0 16 18 1 0 63 55 2 0 63 54 2 0 29 39 1 0 29 14 1 0 42 14 1 0 39 41 1 0 39 30 1 0 21 18 2 0 14 27 2 0 30 15 1 0 27 15 1 0 27 9 1 0 9 1 2 0 9 2 1 0 1 22 1 0 2 8 2 0 22 13 2 0 8 13 1 0 13 65 1 0 1 66 1 0 2 67 1 0 3 68 1 0 4 69 1 0 5 70 1 0 6 71 1 0 7 72 1 0 8 73 1 0 15 74 1 0 15 75 1 0 16 76 1 0 17 77 1 0 18 78 1 0 19 79 1 0 20 80 1 0 21 81 1 0 22 82 1 0 23 83 1 0 29 84 1 0 29 85 1 0 30 86 1 0 30 87 1 0 31 88 1 0 31 89 1 0 32 90 1 0 32 91 1 0 33 92 1 0 33 93 1 0 34 94 1 0 34 95 1 0 35 96 1 0 35 97 1 0 36 98 1 0 36 99 1 0 37100 1 0 37101 1 0 38102 1 0 38103 1 0 40104 1 0 40105 1 0 40106 1 0 41107 1 0 41108 1 0 41109 1 0 42110 1 0 42111 1 0 43112 1 0 43113 1 0 44114 1 0 44115 1 0 45116 1 0 45117 1 0 46118 1 6 49119 1 0 50120 1 0 M END): 23 ms reading 120 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 120 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
|
| Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax. |
|
Read full article at Wikipedia
|
InChI=1S/C47H55ClF3N5O6S3/c1- 46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57)/t38-/m1/s1 |
| JLYAXFNOILIKPP-KXQOOQHDSA-N |
| CC1(C)CCC(=C(CN2CCN(CC2)C2=CC=C(C=C2)C(=O)NS(=O)(=O)C2=CC(=C(N[C@H](CCN3CCOCC3)CSC3=CC=CC=C3)C=C2)S(=O)(=O)C(F)(F)F)C1)C1=CC=C(Cl)C=C1 |
|
|
Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
|
|
|
apoptosis inducer
Any substance that induces the process of apoptosis (programmed cell death) in multi-celled organisms.
B-cell lymphoma 2 inhibitor
Any inhibitor of B-cell lymphoma 2 protein.
|
|
|
antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
|
|
View more via ChEBI Ontology
|
4-{4-[(4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro[biphenyl]-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide
|
|
navitoclax
|
WHO MedNet
|
navitoclax
|
WHO MedNet
|
navitoclax
|
WHO MedNet
|
navitoclaxum
|
WHO MedNet
|
|
A-855071.0
|
ChemIDplus
|
|
ABT 263
|
ChemIDplus
|
|
ABT-263
|
ChemIDplus
|
|
ABT263
|
ChEBI
|
|
923564-51-6
|
CAS Registry Number
|
ChemIDplus
|
Yang H, Chen C, Chen H, Duan X, Li J, Zhou Y, Zeng W, Yang L (2020)
Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis.
Aging 12, 12750-12770 [PubMed:32611834]
[show Abstract]
Cell senescence is a chronic process associated with age-related degenerative diseases such as osteoarthritis (OA). Senescent cells (SnCs) accumulate in the articular cartilage and synovium, leading to OA pathologies. The accumulation of SnCs in the cartilage results in a senescence-associated secretory phenotype (SASP) and age-related inflammation and dysfunction. Selective removal of SnCs by senolytic agent as a therapeutic strategy has been developed recently. In this study, we examined the ability of the senolytic drug ABT263 (navitoclax) to clear SnCs and further evaluated the therapeutic effect of ABT263 on post-traumatic OA. Monolayer and 3D pellet cultured osteoarthritic chondrocytes were used to evaluate the effect of ABT263 in vitro and a DMM rat model was established for in vivo experiments. We found that ABT263 reduced the expression of inflammatory cytokines and promoted cartilage matrix aggregation in OA chondrocyte pellet culture by inducing SnC apoptosis. Moreover, OA pathological changes in the cartilage and subchondral bone in post-traumatic OA rat were alleviated by ABT263 intra-articular injection. These results demonstrated that ABT263 not only improves inflammatory microenvironment but also promotes cartilage phenotype maintenance in vitro. Furthermore, ABT263 might play a protective role against post-traumatic OA development. Therefore, strategies targeting SnC elimination might be promising for the clinical therapy of OA. | Inoue-Yamauchi A, Oda H (2020)
EMT-inducing transcription factor ZEB1-associated resistance to the BCL-2/BCL-XL inhibitor is overcome by BIM upregulation in ovarian clear cell carcinoma cells.
Biochemical and biophysical research communications 526, 612-617 [PubMed:32247610]
[show Abstract]
Ovarian clear cell carcinoma (OCCC) is an aggressive subtype of epithelial ovarian cancer, which generally exhibits chemoresistance. Effective therapy for OCCC is currently unavailable, requiring the development of new therapeutic strategies. ABT-263 (navitoclax), an inhibitor of the anti-apoptotic BCL-2/BCL-XL, has a potent ability of inducing death in cancer cells; however, the therapeutic effect of ABT-263 in OCCC remains unclear. Epithelial cells undergo epithelial-mesenchymal transition (EMT) to acquire a mesenchymal phenotype, which is known to contribute to the development of resistance against therapeutic agents. In this study, we revealed that the sensitivity of OCCC cells to ABT-263 was associated with the epithelial/mesenchymal status of the cells. While the OCCC cells with an epithelial phenotype were ABT-263-sensitive, those with a mesenchymal phenotype were ABT-263-resistant, which was accompanied by an insufficient expression of the pro-apoptotic BH3 protein BIM. Mechanistically, the EMT-inducing transcription factor, ZEB1 down-regulated BIM transcription by binding to BIM promoter, resulting in resistance to ABT-263. It is noteworthy that ZEB1-associated ABT-263 resistance was overcome by an HDAC inhibitor, FK228 (romidepsin), through the up-regulation of BIM. In summary, our study provides evidence for a mechanism for ABT-263 resistance in OCCC cells as well as a potential therapeutic strategy to overcome it. | Lee YC, Wang LJ, Huang CH, Chiou JT, Shi YJ, Chang LS (2020)
Inhibition of EGFR pathway promotes the cytotoxicity of ABT-263 in human leukemia K562 cells by blocking MCL1 upregulation.
Biochemical pharmacology 178, 114047 [PubMed:32446890]
[show Abstract]
ABT-263 induces MCL1 upregulation in cancer cells, which confers resistance to the drug. An increased understanding of the mechanism underlying ABT-263-induced MCL1 expression may provide a strategy to improve its tumor-suppression activity. The present study revealed that ABT-263 reduced the turnover of MCL1 mRNA, thereby upregulating MCL1 expression in human K562 leukemia cells. Furthermore, ABT-263-induced EGFR activation promoted AGO2 phosphorylation at Y393 and reduced miR-125b maturation. Treatment with EGFR inhibitors mitigated MCL1 upregulation induced by ABT-263. Additionally, lithium chloride (LiCl) alleviated ABT-263-induced MCL1 upregulation through EGFR-AGO2 axis-modulated miR-125b suppression. Ectopic expression of dominant negative AGO2(Y393F) or transfection with miR-125b abolished ABT-263-induced upregulation of MCL1 mRNA and protein levels. Co-treatment with either EGFR inhibitors or LiCl collaboratively enhanced ABT-263 cytotoxicity, while MCL1 overexpression eliminated this synergistic effect. Collectively, our data reveal that ABT-263 increases EGFR-mediated AGO2 phosphorylation, which in turn suppresses miR-125b-mediated MCL1 mRNA degradation in K562 cells. The suppression of this signaling pathway results in the synergistic cytotoxic effect of EGFR inhibitors or LiCl and ABT-263. | Ohgino K, Terai H, Yasuda H, Nukaga S, Hamamoto J, Tani T, Kuroda A, Arai D, Ishioka K, Masuzawa K, Ikemura S, Kawada I, Naoki K, Fukunaga K, Soejima K (2020)
Intracellular levels of reactive oxygen species correlate with ABT-263 sensitivity in non-small-cell lung cancer cells.
Cancer science 111, 3793-3801 [PubMed:32687646]
[show Abstract]
ABT-263 (Navitoclax) is a BH3-mimetic drugs targeting anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, thereby inducing apoptosis. In small-cell lung cancer (SCLC) cells, the response to ABT-263 is associated with the expression of myeloid cell leukemia-1 (MCL-1) protein, however the efficacy of ABT-263 in non-small-cell lung cancer (NSCLC) has not been thoroughly evaluated. There are currently no established biomarkers for predicting the efficacy of ABT-263 treatment in NSCLC. We screened a panel of different NSCLC cell lines and found that ABT-263 inhibited cell proliferation and induced apoptosis in Calu-1, Calu-3, and BID007 cells. Inconsistent with previous reports on SCLC, low levels of MCL-1 did not predict the response to ABT-263 in NSCLC cells, however we found that intracellular levels of reactive oxygen species (ROS) in cancer cells were associated with sensitivity to ABT-263 in NSCLC cells. We also showed that increasing the level of intracellular ROS could enhance the sensitivity to ABT-263 in NSCLC cells. In summary, we propose that the intracellular levels of ROS could be used as a potential novel biomarker for predicting a response to ABT-263 in NSCLC. Furthermore, we show some evidence supporting the further assessment of ABT-263 as a new therapeutic strategy in patients with NSCLC combined with agents regulating ROS levels. We believe that our findings and follow-up studies on this matter would lead to novel diagnostic and treatment strategies in patients with NSCLC. | Bellini L, Strub T, Habel N, Pandiani C, Marchetti S, Martel A, Baillif S, Bailly-Maitre B, Gual P, Ballotti R, Bertolotto C (2020)
Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.
Cell death discovery 6, 22 [PubMed:32337074]
[show Abstract]
To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma. | Sharma AK, Roberts RL, Benson RD, Pierce JL, Yu K, Hamrick MW, McGee-Lawrence ME (2020)
The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice.
Frontiers in cell and developmental biology 8, 354 [PubMed:32509782]
[show Abstract]
Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice. This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice. Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (-60.1% females, -45.6% males), and BMSC-derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (-88% females, -83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures (+1.0 to +11.3 fold). Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax's potential (or risk) as a therapeutic agent for combatting age-related musculoskeletal dysfunction and bone loss. | Jia K, Dai Y, Liu A, Li X, Wu L, Lu L, Bao Y, Jin Q (2020)
Senolytic Agent Navitoclax Inhibits Angiotensin II-Induced Heart Failure in Mice.
Journal of cardiovascular pharmacology 76, 452-460 [PubMed:32675749]
[show Abstract]
Navitoclax, which is a type of senolytic drug, selectively eliminates senescent cells. This study aimed to evaluate the therapeutic potential of navitoclax in treatment of angiotensin II (Ang II)-induced heart failure in mice. Navitoclax or vehicle was administrated in mice with Ang II-induced heart failure. Cardiac function and electrophysiology were assessed before and after administration of navitoclax. Cardiac remodeling, including morphological changes, fibrosis, and inflammatory responses, was analyzed in myocardial tissue. Cellular effects of navitoclax were validated in isolated primary cardiomyocytes and cardiac fibroblasts in vitro. Echocardiography of mice showed that navitoclax improved cardiac dysfunction by improving the left ventricular ejection fraction (vehicle: 45.88 ± 2.19%; navitoclax: 54.70 ± 1.65%, P < 0.01). In cardiac electrophysiological testing, navitoclax increased conduction velocity (vehicle: 1.37 ± 0.05 mm/ms; navitoclax: 1.69 ± 0.08 mm/ms, P < 0.05) and decreased susceptibility to ventricular tachyarrhythmia induced by programmed electrical stimulation. Histopathological staining, immunofluorescence, and western blotting examinations showed that navitoclax ameliorated Ang II-induced cardiac fibrosis, hypertrophy, and the inflammatory response. Moreover, navitoclax eliminated senescent cells by inducing apoptosis. Therefore, navitoclax improved cardiac function and electrophysiological characteristics through decreasing cardiac fibrosis, hypertrophy, and inflammation in mice with heart failure. Pharmacological clearance of senescent cells may be a potential therapeutic approach in heart failure with reduced ejection fraction. | Saleh T, Carpenter VJ, Tyutyunyk-Massey L, Murray G, Leverson JD, Souers AJ, Alotaibi MR, Faber AC, Reed J, Harada H, Gewirtz DA (2020)
Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-XL -BAX interaction.
Molecular oncology 14, 2504-2519 [PubMed:32652830]
[show Abstract]
Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT-263 (navitoclax), therefore providing a "two-hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy-induced senescence and ABT-263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL-XL and BAX. The administration of ABT-263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor-bearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence. | Murray JB, Davidson J, Chen I, Davis B, Dokurno P, Graham CJ, Harris R, Jordan A, Matassova N, Pedder C, Ray S, Roughley SD, Smith J, Walmsley C, Wang Y, Whitehead N, Williamson DS, Casara P, Le Diguarher T, Hickman J, Stark J, Kotschy A, Geneste O, Hubbard RE (2019)
Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.
ACS omega 4, 8892-8906 [PubMed:31459977]
[show Abstract]
We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K d of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization. | Li H, Wang H, Deng K, Han W, Hong B, Lin W (2019)
The ratio of Bcl-2/Bim as a predictor of cisplatin response provides a rational combination of ABT-263 with cisplatin or radiation in small cell lung cancer.
Cancer biomarkers : section A of Disease markers 24, 51-59 [PubMed:30614795]
[show Abstract]
BackgroundCisplatin-based chemotherapy and radiotherapy are the most commonly used treatments for small cell lung cancer (SCLC). However, despise initially dramatic response, the response duration of SCLC patients is variable and resistance to chemo- and radio-therapy inevitably develops.ObjectiveThe aim of the study is to investigate the role of Bcl-2 family proteins in predicting SCLC sensitivity to cisplatin treatment, and to identify the potential sensitizer of cisplatin or ratiation treatment in SCLC.MethodsWe collected cisplatin sensitivity data from public available database, and evaluated its possible association with mRNA or protein expression of Bcl-2 family members in SCLC cell lines.ResultsThe IC50 value of cisplatin was significantly correlated with the ratio of Bcl-2/Bim mRNA expression in 33 SCLC cell lines (P= 0.041) as well as the ratio of Bcl-2/Bim protein expression in 7 SCLC cell lines (P= 0.0252). Furthermore, a BH3-mimetic ABT-263 was found to be able to sensitize SCLC cells to cisplatin or radiation. The synergistic and additive antitumor activity of ABT-263 combined with cisplatin or radiation was associated with the enhanced apoptosis, which may be caused by the disruption of Bcl-2 binding to Bim by ABT-263.ConclusionsOur study indicates that the ratio of Bcl-2/Bim could be a SCLC response predictor to cisplatin, and ABT-263 addition could be an effective strategy to improve the activity of chemo- or radio-therapy in SCLC. | Zhan Y, Wang Y, Qi M, Liang P, Ma Y, Li T, Li H, Dai C, An Z, Qi Y, Wu H, Shao H (2019)
BH3 mimetic ABT-263 enhances the anticancer effects of apigenin in tumor cells with activating EGFR mutation.
Cell & bioscience 9, 60 [PubMed:31367332]
[show Abstract]
BackgroundMutated epidermal growth factor receptor (EGFR) is one of the most successful targets in cancer targeted therapy. While this treatment has benefited many patients with an activating EGFR mutation (EGFRm), almost all those who initially benefited will eventually develop acquired drug resistance (ADR) after a certain period of time. New therapeutic strategies need to be explored to treat EGFRm tumors and overcome or minimize this recurring ADR.ResultsOur data showed that apigenin alone has only mild inhibitory effects on EGFRm tumor cells. By drug screening, we found that ABT-263 can significantly enhance the antitumor activities of apigenin in tumor cells harbouring an activating EGFR mutation and AZD9291-resistant H1975 cells. Mechanistically, apigenin upregulated the expression of Noxa in EGFRm tumor cells by targeting the AKT-FoxO3a pathway, thereby synergizing with ABT-263 to suppress tumor cell growth and proliferation in vitro and in vivo.ConclusionsOur study provides a rationale for the clinical application of the combination treatment of apigenin and BH3 mimetics in the treatment of EGFRm tumors. | Huang T, Ding X, Xu G, Chen G, Cao Y, Peng C, Shen S, Lv Y, Wang L, Zou X (2019)
CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263.
Cell death & disease 10, 602 [PubMed:31399555]
[show Abstract]
Cholangiocarcinoma (CCA) is a fatal disease without effective targeted therapy. We screened a small-molecule library of 116 inhibitors targeting different targets of the cell cycle and discovered several kinases, including Cyclin-dependent kinase 7 (CDK7) as vulnerabilities in CCA. Analysis of multiple CCA data sets demonstrated that CDK7 was overexpressed in CCA tissues. Further studies demonstrated that CDK7 inhibitor THZ1 inhibited cell viability and induced apoptosis in CCA cells. We also showed that THZ1 inhibited CCA cell growth in a xenograft model. RNA-sequencing followed by Gene ontology analysis showed a striking impact of THZ1 on DNA-templated transcriptional programs. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition. A number of oncogenic transcription factors and survival proteins, like MCL1, FOSL1, and RUNX1, were repressed by THZ1. MCL1, one of the antiapoptotic BCL2 family members, was significantly inhibited upon THZ1 treatment. Accordingly, combining THZ1 with a BCL2/BCL-XL inhibitor ABT-263 synergized in impairing cell growth and driving apoptosis. Our results demonstrate CDK7 as a potential target in treating CCA. Combinations of CDK7 inhibition and BCL2/BCL-XL inhibition may offer a novel therapeutic strategy for CCA. | Yang IH, Jung JY, Kim SH, Yoo ES, Cho NP, Lee H, Lee JY, Hong SD, Shin JA, Cho SD (2019)
ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein.
Cellular oncology (Dordrecht, Netherlands) 42, 357-368 [PubMed:30919222]
[show Abstract]
PurposeABT-263 is a potent BH3 mimetic that possesses anticancer potential against various types of cancer. In general, this potential is due to its high binding affinity to anti-apoptotic proteins in the Bcl-2 family that disrupt sequestration of pro-apoptotic proteins. In the present study, we sought to identify an alternative regulatory mechanism responsible for ABT-263-mediated anticancer activity in human oral cancer.MethodsWe investigated the in vitro anti-cancer effects of ABT-263 using a trypan blue exclusion assay, Western blotting, DAPI staining, immunofluorescence staining, a live/dead assay, microarray-based expression profiling, and quantitative real-time PCR. In vivo anti-tumorigenic effects of ABT-263 were examined using a nude mouse tumor xenograft model, a TUNEL assay, and immunohistochemistry.ResultsWe found that ABT-263 suppressed viability and induced apoptosis in human oral cancer-derived cell lines HSC-3 and HSC-4. Subsequent microarray-based gene expression profiling revealed 55 differentially expressed genes in the ABT-263-treatead group, including 12 genes associated with "endoplasmic reticulum stress and apoptosis." Consistent with the microarray results, the mRNA expression levels of the top four genes (CHOP, TRB3, ASNS, and STC2) were found to be significantly increased. In addition, we found that ABT-263 considerably enhanced the expression levels of the C/EBP-homologous protein (CHOP) and its mRNA, resulting in apoptosis induction in four other human oral cancer-derived cell lines (MC-3, YD-15, HN22, and Ca9.22). Extending our in vitro findings, we found that ABT-263 reduced the growth of HSC-4 cells in vivo at a dosage of 100 mg/kg/day without any change in body weight. TUNEL-positive cells were also found to be increased in tumors of ABT-263-treated mice without any apparent histopathological changes in liver or kidney tissues.ConclusionsThese results provide evidence that ABT-263 may serve as an effective therapeutic agent for the treatment of human oral cancer. | Dastur A, Choi A, Costa C, Yin X, Williams A, McClanaghan J, Greenberg M, Roderick J, Patel NU, Boisvert J, McDermott U, Garnett MJ, Almenara J, Grant S, Rizzo K, Engelman JA, Kelliher M, Faber AC, Benes CH (2019)
NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.
Clinical cancer research : an official journal of the American Association for Cancer Research 25, 312-324 [PubMed:30224339]
[show Abstract]
PurposeEffective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.Experimental designWe performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both in vitro experiments and in vivo studies on patient-derived xenograft models.ResultsWe found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax in vitro and leads to tumor regressions in vivo.ConclusionsOur results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance. | Lever JR, Fergason-Cantrell EA (2019)
Allosteric modulation of sigma receptors by BH3 mimetics ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax).
Pharmacological research 142, 87-100 [PubMed:30721730]
[show Abstract]
ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax) are under intensive preclinical and clinical investigation as treatments for hematologic and other malignancies. These small molecules mimic pro-death B-cell lymphoma-2 (Bcl-2) Homology 3 (BH3) domain-only proteins. They also bear a structural resemblance to certain sigma (σ) receptor ligands. Moreover, the Bcl-2 and σ receptor protein families are both located primarily at the endoplasmic reticulum, mediate cell death and survival through protein-protein interactions, and physically associate. Accordingly, we examined the ability of the ABT series of BH3 mimetics to interact with σ receptors using radioligand-binding techniques. Negative allosteric modulation of [3H](+)-pentazocine, an agonist, binding to σ1 receptors in guinea pig brain membranes was observed for ABT-737, ABT-263 and ABT-199. Findings included reduction of specific binding to distinct plateaus in concentration-dependent fashion, significant slowing of radioligand dissociation kinetics, and decreases in radioligand affinity with no or modest changes in maximal receptor densities. Using a ternary complex model, dissociation constants (KX) for modulator binding to the σ1 receptor ranged from 1 to 2.5 μM, while negative cooperativity factors (α), representing the changes in affinity of ligand and modulator when bound as a ternary complex with the receptor, ranged from 0.15 to 0.42. These observations were extended and reinforced by studies using intact small cell (NCI-H69) and non-small cell (NCI-H23) lung cancer cells, and by using an antagonist σ1 receptor radioligand, E-N-1-(3'-[125I]iodoallyl)-N'-4-(3″,4″-dimethoxyphenethyl)piperazine, in mouse brain membranes. By contrast, exploratory studies indicate marked enhancement of the σ2 receptor binding of [3H]1,3-di-(o-tolyl)guanidine/(+)-pentazocine in NCI-H23 cells and guinea pig brain membranes. These findings raise intriguing questions regarding mechanism and potential functional outcomes. | Britt EL, Raman S, Leek K, Sheehy CH, Kim SW, Harada H (2019)
Combination of fenretinide and ABT-263 induces apoptosis through NOXA for head and neck squamous cell carcinoma treatment.
PloS one 14, e0219398 [PubMed:31276572]
[show Abstract]
The overall survival for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) remains low, with little progress made over decades. Cisplatin, most frequently used for HNSCC treatment, activates mitochondria-dependent apoptosis through the BCL-2 family proteins. We have previously demonstrated that the pro-apoptotic BH3-only protein, NOXA plays a critical role in this process. NOXA binds and inactivates anti-apoptotic MCL-1, while the BCL-2 inhibitor ABT-263 is capable of inactivating anti-apoptotic BCL-2 and BCL-XL. We hypothesized that combination of NOXA and ABT-263 treatment increases cell death by simultaneously inhibiting anti-apoptotic BCL-2 family proteins in HNSCC cells. Here, we demonstrated that combination of ectopic NOXA expression and ABT-263 enhanced apoptosis in p53-inactive, p53 wild-type, and human papillomavirus (HPV)-positive HNSCC cell lines. Furthermore, a retinoid derivative and an endoplasmic reticulum stress inducer, fenretinide, induced NOXA, and combination of fenretinide and ABT-263 strongly induced apoptosis in HNSCC cells regardless of the HPV or p53 statuses. We also found that MCL-1 and BCL-XL are the primary targets of apoptosis induced by the combinations. These results will develop novel and alternative therapeutic strategies to directly modify the cell death machinery in HNSCC. | Lian BSX, Yek AEH, Shuvas H, Abdul Rahman SF, Muniandy K, Mohana-Kumaran N (2018)
Synergistic anti-proliferative effects of combination of ABT-263 and MCL-1 selective inhibitor A-1210477 on cervical cancer cell lines.
BMC research notes 11, 197 [PubMed:29580266]
[show Abstract]
ObjectiveThere are number of studies which report that BCL-2 anti-apoptotic proteins (e.g. BCL-2, BCL-XL, and MCL-1) are highly expressed in cervical cancer tissues compared to the normal cervical epithelia. Despite these reports, targeting these proteins for cervical cancer treatment has not been explored extensively. BH3-mimetics that inhibit specific BCL-2 anti-apoptotic proteins may hold encouraging treatment outcomes for cervical cancer management. Hence, the aim of this pilot study is to investigate the sensitivity of cervical cancer cell lines to combination of two BH3-mimetics namely ABT-263 which selectively inhibits BCL-2, BCL-XL and BCL-w and A-1210477, a selective MCL-1 inhibitor.ResultsWe report that combination of A-1210477 and ABT-263 exhibited synergistic effects on all cervical cancer cell lines tested. Drug sensitization studies revealed that A-1210477 sensitised the cervical cancer cell lines SiHa and CaSki to ABT-263 by 11- and fivefold, respectively. Sensitization also occurred in the opposite direction whereby ABT-263 sensitised SiHa and CaSki to A-1210477 by eightfold. This report shows that combination of ABT-263 and A-1210477 could be a potential treatment strategy for cervical cancer. Extensive drug mechanistic studies and drug sensitivity studies in physiological models are necessary to unleash the prospect of this combination for cervical cancer therapy. | Lee YC, Wang LJ, Huang CH, Shi YJ, Chang LS (2018)
ABT-263-induced MCL1 upregulation depends on autophagy-mediated 4EBP1 downregulation in human leukemia cells.
Cancer letters 432, 191-204 [PubMed:29913235]
[show Abstract]
The present study aimed to investigate the pathway related to MCL1 expression in ABT-263-treated human leukemia U937 cells. ABT-263 upregulated MCL1 protein expression but did not affect its mRNA level and protein stability. Notably, ABT-263 increased 4EBP1 mRNA decay and thus reduced 4EBP1 expression. Overexpression of 4EBP1 abrogated ABT-263-induced MCL1 upregulation. ABT-263-induced activation of IKKα/β-NFκB axis elicited autophagy of U937 cells, leading to reduced mRNA stability of 4EBP1. Inhibition of the IKKα/β-NFκB axis or autophagy mitigated the effect of ABT-263 on 4EBP1 and MCL1 expression. Amsacrine enhanced the cytotoxicity of ABT-263 in human leukemia U937, HL-60, and Jurkat cells because of its inhibitory effect on the IKKα/β-NFκB-mediated pathway. Our data indicate that ABT-263 alleviates the inhibitory effect of 4EBP1 on MCL1 protein synthesis through IKKα/β-NFκB-mediated induction of autophagy, and suggest a promising strategy to improve anti-leukemia therapy with ABT-263. | Balakrishnan I, Madhavan K, Pierce A, Dahl N, Lemma R, Fosmire S, Wang D, Prince E, Alimova I, Hashizume R, Huellman E, Hawkins C, Carcaboso A, Gupta N, Monje M, Jones K, Green A, Foreman N, Vibhakar R, Venkataraman S (2018)
DIPG-55. TARGETING SENESCENT CELLS WITH ABT-263 ENHANCES CELL DEATH INDUCED BY BMI1 INHIBITION AND IONIZING RADIATION IN DIPG
Neuro-oncology 20, i60-i60 [PubMed Central:PMC6011937]
[show Abstract]
Abstract Ionizing Radiation (IR) is a key treatment modality for DIPG, but it provides only temporary relief as the tumor cells develop resistance to radiation. Recently, we and others have shown that inhibition of BMI1 either alone or in combination with radiation attenuates DIPG cell proliferation in vitro. While we are demonstrating the in vivo efficacy of pharmacological inhibition of BMI1 and understanding the mechanism of anti-tumor effect of BMI1 inhibition in DIPG, the existence of treatment-resistant cells remains a major obstacle for a prolonged cure. Both IR and genetic or pharmacological inhibition of BMI1 induces cellular senescence as a mechanism to suppress tumor cell proliferation, implying that senescence can be considered as tumor suppressor. Paradoxically, recent studies have shown that accelerated senescence can mediate tumor recurrence due to the development of pro-oncogenic environment. In line with this, we are investigating whether clearance of treatment-induced senescent cells enhances treatment outcomes. DIPG cells exposed to different doses of radiation followed by treatment with ABT-263 (Navitoclax), a drug which selectively clears the senescent cells, resulted in increased radiosensitization. Treatment of pre-radiated DIPG cells with ABT-263 decreased the activity of senescence-associated beta-galactosidase and anti-apoptotic protein expression. Similarly, chemical inhibition of BMI1 in combination with ABT-263 showed synergistic killing of DIPG cells. The synergy was most pronounced in DIPG cells harboring wildtype p53. Our study highlights the importance of eliminating treatment-induced senescent cells while inhibiting proliferation of DIPG tumors, a combination which can immensely improve therapeutic efficacy in DIPG patients. | Ketchem CJ, Kucera C, Barve A, Beverly LJ (2018)
The Antiarrhythmic Drug, Amiodarone, Decreases AKT Activity and Sensitizes Human Acute Myeloid Leukemia Cells to Apoptosis by ABT-263.
The American journal of the medical sciences 355, 488-496 [PubMed:29753379]
[show Abstract]
BackgroundSuccessful treatment of leukemia requires new medications to combat drug resistance, but the development of novel therapies is an arduous and risky endeavor. Repurposing currently approved drugs or those already in clinical development to treat other indications is a more practical approach. Moreover, combinatorial therapeutics are often more efficacious than single agent therapeutics because the former can simultaneously target multiple pathways that mitigate tumor aggressiveness and induce cancer cell death.Material and methodsIn this study, we combined the class III antiarrhythmic agent amiodarone and the BH3 mimetic ABT-263 based on data from a prior drug screen to assess the degree of apoptotic induction in 2 human leukemia cell lines.ResultsThe combination yielded statistically significant increases in apoptosis in both cell lines by downregulating AKT activity and increasing cleaved caspase-3.ConclusionsOverall, our findings suggest that combining K+ channel blockers with prosurvival Bcl-2 family inhibitors is a promising therapeutic approach in treating leukemia. | Lee EY, Gong EY, Shin JS, Moon JH, Shim HJ, Kim SM, Lee S, Jeong J, Gong JH, Kim MJ, Lee DH, Park YS, Shin J, Hong SW, Kim YS, Jin DH (2018)
Human breast cancer cells display different sensitivities to ABT-263 based on the level of survivin.
Toxicology in vitro : an international journal published in association with BIBRA 46, 229-236 [PubMed:28947240]
[show Abstract]
ABT-263 (navitoclax), a Bcl-2 family protein inhibitor, was clinically tested as an anti-cancer agent. However, the clinical trials were limited given the occurrence of resistance to monotherapy in breast cancer cells. Our study investigates the mechanisms for overcoming navitoclax resistance by combining it with an mTOR inhibitor to indirectly target survivin. The apoptotic effects of navitoclax occurred in MDA-MB-231 breast cancer cells in a time- and dose-dependent fashion, but MCF-7 cells were resistant to navitoclax treatment. The expression of Bcl-2 family genes was not altered by navitoclax, but the expression of survivin, a member of the inhibitors of apoptosis proteins (IAP) family, was downregulated, which increased death signaling in MDA-MB-231 cells. In MCF-7 cells, a navitoclax-resistant cell line, combined treatment with navitoclax and everolimus synergistically reduced survivin expression and induced cell death. These data indicate that navitoclax induces cell death in MDA-MB-231 cells but not in MCF-7 cells. Decreased survivin expression in MDA-MB-231 cells may be a primary pathway for death signaling. Combined navitoclax and everolimus treatment induces cell death by reducing the stability of survivin in MCF-7 cells. Given that survivin-targeted therapy overcomes resistance to navitoclax, this strategy could be used to treat breast cancer patients. | Lin QH, Que FC, Gu CP, Zhong DS, Zhou D, Kong Y, Yu L, Liu SW (2017)
ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro.
Acta pharmacologica Sinica 38, 1632-1641 [PubMed:28713162]
[show Abstract]
Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC50 values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 μmol/L) dose-dependently induced G1/G0-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G1/G0-phase arrest. Knockdown of p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity. | Wang H, Hong B, Li X, Deng K, Li H, Yan Lui VW, Lin W (2017)
JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer.
Oncotarget 8, 86312-86324 [PubMed:29156797]
[show Abstract]
Small cell lung cancer (SCLC) is a clinically aggressive cancer with very poor prognosis. Amplification of MYC family genes and overexpression of Bcl-2 protein are common in SCLC, and they are likely therapeutic targets for SCLC. Previous clinical study showed that single agent targeting Bcl-2 with ABT-263 was of limited efficacy in SCLC. In this study, we demonstrated for the first time that co-targeting of N-Myc and Bcl-2 resulted in marked synergistic antitumor effects in MYCN-amplified SCLC. We found that MYCN-amplified SCLC cells were highly sensitive to a Bromodomain and Extra-Terminal domain (BET) inhibitor JQ1, which was able to inhibit N-Myc protein expression. The inhibition of N-Myc by JQ1 induced the expression of Bim, and thereby sensitizing MYCN-amplified SCLC cells to ABT-263. The knockdown on Bim by siRNA reduced this JQ1/ABT-263 induced cell death. ABT-263 and JQ1 co-treatment in MYCN-amplified SCLC cells markedly disrupted Bim/Bcl-2 interaction, and prevented Bim's interaction with Mcl-1. Importantly, this JQ1/ABT-263 co-targeting substantially inhibited the growth of MYCN-amplified SCLC xenografts in vivo. Our study demonstrates a new JQ-1/ABT-263 co-targeting strategy that can be employed for MYCN-amplified SCLC with high efficacy. | Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA, Sakai N, Kuehl T, Ryan J, Bhola P, Montero J, Kapoor M, Baron M, Varelas X, Tschumperlin DJ, Letai A, Tager AM (2017)
Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.
Science translational medicine 9, eaal3765 [PubMed:29237758]
[show Abstract]
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-XL to sequester BIM and ensure myofibroblast survival. Myofibroblasts become particularly susceptible to apoptosis induced by "BH3 mimetic" drugs inhibiting BCL-XL such as ABT-263. ABT-263 displaces BCL-XL binding to BIM, allowing BIM to activate apoptosis on stiffness-primed myofibroblasts. Therapeutic blockade of BCL-XL with ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases. | Nakajima W, Sharma K, Hicks MA, Le N, Brown R, Krystal GW, Harada H (2016)
Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer.
Cancer biology & therapy 17, 27-35 [PubMed:26575826]
[show Abstract]
Small cell lung cancer (SCLC) is an aggressive tumor type with high mortality. One promising approach for SCLC treatment would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis. BH3 mimetic antagonists, such as ABT-737 and its orally available derivative ABT-263 (navitoclax) have been developed to block the function of pro-survival BCL-2 family members. The sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of sensitivity to ABT-737. Thus, pharmacological up-regulation of Noxa could enhance cell death induced by the BH3 mimetics. We find that the combination of ABT-263 and a HDAC inhibitor, vorinostat, efficiently induces apoptosis in a variety of SCLC cell lines, including ABT-263 resistant cell lines. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by down-regulation of BCL-XL and release of BAK from BCL-XL and MCL-1. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative and effective regimen for SCLC treatment. | Green MM, Shekhar TM, Hawkins CJ (2016)
Data on the DNA damaging and mutagenic potential of the BH3-mimetics ABT-263/Navitoclax and TW-37.
Data in brief 6, 710-714 [PubMed:26958630]
[show Abstract]
Unfortunately, the mutagenic activities of chemotherapy and radiotherapy can provoke development of therapy-induced malignancies in cancer survivors. Non-mutagenic anti-cancer therapies may be less likely to trigger subsequent malignant neoplasms. Here we present data regarding the DNA damaging and mutagenic potential of two drugs that antagonize proteins within the Bcl-2 family: ABT-263/Navitoclax and TW-37. Our data reveal that concentrations of these agents that stimulated Bax/Bak-dependent signaling provoked little DNA damage and failed to trigger mutations in surviving cells. The data supplied in this article is related to the research work entitled "Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells" [1]. | Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW (2013)
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
Nature medicine 19, 202-208 [PubMed:23291630]
[show Abstract]
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers. | Lock R, Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Wu J, Smith MA (2008)
Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program.
Pediatric blood & cancer 50, 1181-1189 [PubMed:18085673]
[show Abstract]
BackgroundABT-263 is a potent (K(i) < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-x(L) and Bcl-w. The structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation.MethodsABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 microM using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days.ResultsABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC(50) for all of the lines in the panel was 1.91 microM. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation.ConclusionsABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel. |
|
