Table 1.
Consequences of UPR induction by drugs in leukemic cells. For each drug, the chemical nature, the pubchem compound ID, and the molecular target are provided when available. The type of leukemia on which the work was carried out was provided as well as the inferred or demonstrated role of UPR activation. The involved effectors are also indicated, when they have been identified (n.d.: not determined).
| Molecule | Chemical Nature | Pubchem Compound CID | Target | Type of Leukemia | Proposed Role of ER Stress/UPR Activation | Mainly Implicated Pathways/Effectors | Ref. |
|---|---|---|---|---|---|---|---|
| BIX-01294 | 25150857 | Histone methyltransferase G9A | AML | Adaptive | PERK (prosurvival, via NRF2) | [170] | |
| SCH727965 (Dinaciclib) | 46926350 | CDKs 1,2,5 and 9 | AML, CML, T-ALL | Adaptive | XBP1s | [171] | |
| Ski, ROMe | 16760659 | spingosine kinases 1 and 2 | T-ALL | Adaptive | unclear | [172] | |
| MDA-7/IL-24) | cytokine | - | n.d. | AML, APL | Adaptive | GRP78/Bip, IRE1α, GADD34 | [173] |
| sorafenib | multikinase inhibitor | 216239 | MEK/ERK pathway | U937 cell line | Adaptive | PERK | [174] |
| Digoxine | cardiac glycoside | 2724385 | Na+/K+ ATPase | K562 (erythroleukemic) and THP-1 (acute monocytic leukemia) cell lines | Adaptive | PERK, IRE1α | [175] |
| Shikonin | naphthoquinone | 479503 | pyruvate kinase-M2 (PKM2), proteasome inhibition, NFkB, Thioredoxin reductase (TrxR1) | HL60 | Adaptive | ERP57 and Calreticulin | [176] |
| 3-deazaneplanocin A (DZNeP) | cyclopentenyl analog of 3-deazaadenosine | 73087 | histone methyltransferase | MV4-11, MOLM-14, Mono-Mac-1, THP-1, HL60 and KG-1 AML cell lines | Adaptive | GRP78, GRP94, PERK, PDIA isoform 3, 4, and 5 | [177] |
| wolfberry phytochemicals | n.d. | - | n.d. | Jurkat cell line | Adaptive | all UPR pathways | [178] |
| Imatinib | 5291 | tyrosine kinases inhibitor | CML/LAMA-84 CML cell line and murine myeloid progenitor primary cells | The constitutive activation of PERK in CML cells protects from imatinib treatment | PERK | [162] | |
| Metformin | 4091 | multiple, see PMID: 28776086 | T-ALL, B-ALL | Switch form adaptive to terminal | IRE1α, CHOP | [179] | |
| Nilotinib + MKC8866 | 644241 | Tyrosine kinases (Nilotinib); IRE1α (MKC8866) | ALL (Ph+) | Switch form adaptive to terminal | IRE1α (cytoprotective); PERK and ATF6α (cytotoxic) | [169] | |
| 2-deoxy-D-glucose | glucose analog | 108223 | n.d. | ALL Cell Lines | Switch form adaptive to terminal | GRP78/Bip, CHOP | [180,181] |
| Selenite | sodium selenite | 24934 | n.d. | NB4 cell line (APL) | Switch form adaptive to terminal | PERK/eIF2α/ATF4 | [182] |
| Asperuloside | iridoid glycoside | 84298 | n.d. | cell lines HL60 and U937, primary leukemic cells | Terminal: apoptosis induction | all UPR pathways | [183] |
| JA3 & JA7 | Aldehyde biphenyl chalcones | 134820953 | n.d. | (AML); T-ALL; CML | Terminal: immunogenic apoptosis-like cell death | CHOP; PERK | [184] |
| Oprozomib | tripeptide analog of carfilzomib | 25067547 | immunoproteasome subunit β5i/LMP7 (ubiquitin–proteasome pathway) | CML | Terminal: apoptosis induction | PERK, IRE1α (via ASK/JNK/Bim) | [185] |
| VAS3947 | given in [186] fig 1a | 7471335 | NADPH oxidases | AML | Terminal: apoptosis induction | IRE1α, PERK | [186] |
| Arsenic trioxide + Gilteritinib | 14888/49803313 | FLT3 (for Gilteritinib) | AML (FLT3-ITD) | Terminal: apoptosis induction | IRE1α | [187] | |
| GSK-J4 | 71729975 | H3K27me3 demethylase | AML | Terminal: apoptosis induction | PKCα; Bcl2 phosphorylation | [188] | |
| CXL146 | 4H-chromene derivative | - | AML (or APL): HL60; CML | Terminal: apoptosis induction | PERK, IRE1α, ATF6α | [189] | |
| FF-10501 | given in paper | 124343 | inosine monophosphate deshydrogenase | AML | Terminal: necrotic cell death | CHOP | [190] |
| Retinoic acid+Tunicamycin+ arsenic trioxide | 444795/11104835 | n.d. | AML | Terminal: Cytotoxic UPR | CHOP, XBP1s | [191] | |
| [Retinoic acid or arsenic trioxide] + tunicamycin | 444795/11104835 | n.d. | APL | Terminal: Cytotoxic UPR | [192] | ||
| MIM1 and UMI-77 | 135691163/992586 | n.d. | AML; T-ALL | Terminal: Cytotoxic UPR | NOXA | [193] | |
| PFR | peptide | - | n.d. | AML | Terminal: necroptosis | [193] | |
| Genistein | Isoflavone | 5280961 | n.d. | AML or APL (HL60 cell line) | Terminal: Cytotoxic UPR | [194] | |
| Camalexin | Phytoalexin (structure given in paper) | 636970 | n.d. | AML | Terminal: apoptosis induction | PERK, CHOP | [195] |
| Ibrutinib (PCI-32765) | 24821094 | Bruton’s tyrosine kinase | B-ALL | Terminal: apoptosis induction | ATF4; CHOP | [196] | |
| OT-55 | bis-coumarine derivative | - | n.d. | CML | Terminal: Immunogenic cell death induction; apoptosis induction | not well documented | [197] |
| RS-F3 | fistularin-3 stereoisomer | - | AML | Terminal: Cytotoxic UPR (assumed) | PERK; XBP1s; CHOP | [198] | |
| Bardoxolone methyl (CDDO-Me) | triterpenoid | 400769 | Nrf2 and NF-κB | Chronic myeloid leukemia, K562 cell line | Terminal: apoptosis induction | PERK, IRE1α, CHOP | [199] |
| 3-O-trans-p-coumaroyl-alphitolic acid (3OTPCA) | triterpenoid | - | n.d. | U937, Molt-4 and Jurkat cell lines. | Terminal: apoptosis induction | XBP-1 and CHOP | [200] |
| Nelfinavir | 64143 | HIV protease inhibitors | T-ALL, B-ALL, and AML; CLL primary leukemic cells | Terminal: apoptosis induction; In CLL, contributes to the induction of cell death in choroquine treated cells | CHOP | [201,202] | |
| CB-5083 | 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide | 439268 | Valosin-Containing Protein/p97 | B-ALL Cell Lines (BALL1, REH, NALM6, OP1, ALL-PO, 697, RS4;11, BV173, SEM, and SUPB15) | Terminal: apoptosis induction | all UPR pathways | [203] |
| Tunicamycin ± Quizartinib (AC220) | AC220 | 11104835 + 24889392 | FLT3 | AML (FLT3-ITD) | Terminal: apoptosis induction | PERK, CHOP | [204] |
| Cryptotanshinone | lipophilic diterpene quinone | 160254 | n.d. | CCRF-CEM cell line (ALL) | Terminal: apoptosis induction | IRE1α-XBP1, PERK-eIF2α-ATF4 | [205] |
| Oxalicumone A | dihydrothiophene-condensed sulfur chromone | 90676613 | n.d. | KG-1a, HL60, U937, and K562 cell lines (AML) | Terminal: apoptosis induction | IRE1α-XBP1, PERK--CHOP | [206] |
| Pevonedistat (MLN4924) | adenosine sulfamate analog | 16720766 | NEDD8-activating enzyme | T-ALL (CCRF-CEM, Jurkat) and B-ALL (REH, NALM6, SupB15) cell lines | Terminal: apoptosis induction | all UPR pathways | [166] |
| Carfilzomib (PR-171) | tetrapeptide epoxyketone | 11556711 | ubiquitin–proteasome pathway | CLL MEC1 and MEC2 cell lines and primary leukemic cells | Terminal: apoptosis induction | ATF4, CHOP | [207] |
| Miltirone | abietane-type norditerpenoid quinone | 160142 | n.d. | Jurkat, U937, AML and ALL primary leukemic cells | Terminal: apoptosis induction | PERK | [208] |
| Arsenic trioxide | 14888 | n.d. | NB4 cell line (AML)/CML | Terminal: apoptosis induction | IRE1α-XBP1/GRP78/Bip, CHOP, Xbp1 (unspliced…) | [209,210] | |
| JPH203 | O-[(5-Amino-2-phenyl-7-benzoxazolyl)methyl]-3,5-dichloro-L-tyrosine dihydrochloride | 24853505 | LAT1 (L-type amino-acid transporter 1) | Ke37, DND41, Sil-ALL, Peer, Molt-16, Jurkat and SupT1 T-ALL cell lines | Terminal: apoptosis induction | CHOP | [211] |
| Wogonin | 5,7-dihydroxy-8-methoxyflavone | 5281703 | n.d. | HL-60 cell line. | Terminal: apoptosis induction | all UPR pathways-CHOP | [212] |
| Farnesol | acyclic sesquiterpene alcohol | 445070 | n.d. | Molt4 T-ALL cell line | Terminal: apoptosis induction | PERK-eIF2α-ATF3/4 | [213] |
| APO866 | (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide | 6914657 | nicotinamide phosphoribosyltransferase (NAMPT) | OCI/AML2, OCI/AML3, HL-60, HEL, KG1a, SET1, MV4-11, MEC.1, MEC.2, LAMA-84 cell lines and B-CLL and AML primary leukemic cells | Terminal: apoptosis induction | IRE1α-CHOP | [214] |
| Bortezomib | boronic acid | 387447 | proteasome (26S) | NB4 cell line (APL) | Terminal: apoptosis induction | Nd | [215] |
| CX-4945 | 5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid | 24748573 | casein kinase 2 | T-ALL cell lines and primary cells | Terminal: apoptosis induction | GRP78/BIP-IRE1α-CHOP | [216] |
| compound 3 (Pyrimidine analogue) | 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one | - | n.d. | L1210, CEM, JURKAT cell line (ALL) | Terminal: apoptosis induction | CHOP and caspase-12 | [217] |
| R7, R13 | Naphtylchalcones | n.d. | murine lymphoblastic leukemia | Terminal: apoptosis induction (assumed) | CHOP | [218] | |
| S1 (BH mimetic) | APL | Terminal: cytotoxic through NOXA induction | PERK; XBP1s, NOXA | [219] | |||
| Gossypol (BH3 mimetic) | polyphenol | 3503 | phospholipase A2 | AML, APL | Terminal: cytotoxic through NOXA induction | PERK; NOXA | [220] |
| Cariporide | 151172 | Na + H+ exchanger 1 (NHE1) | CML, APL, T-ALL | Terminal: sensitizes to extrinsic, TRAIL-induced, apoptosis | CHOP | [221] | |
| Auranofin | 6333901 | thioredoxin reductase | CLL | Terminal: contributes to the induction of cell death in treated cells | PERK; XBP1s, CHOP | [222] | |
| [Cu(thp)4][PF6] | phosphine copper(I) complex | n.d. | B-ALL | Terminal: apoptosis induction | Xbp1s, CHOP | [223] | |
| Z-Leu-Leu-Nle-CHO | leupeptin analog | - | γ-Secretase | CLL primary leukemic cells | Terminal: apoptosis induction | IRE1α, CHOP | [224] |
| curcumin | Diferuloylmethane | 969516 | n.d. | WEHI-3 myelomonocytic leukemia cell line/NB4 and UF-1 APL cell lines/HL60 cell line | Terminal: apoptosis induction | IRE1α, ATF6α, CHOP/PERK, CHOP, ASK | [225,226,227] |
| LQB 118 | pterocarpanquinone | 46233300 | n.d. | K562 and Jurkat cell lines | Terminal: apoptosis induction (assumed) | caspase 12 | [228] |
| Flavopiridol | Flavonoid alkaloid | 5287969 | CDKs inhibitor | CLL primary leukemic cells | Terminal: contributes to the induction of cell death in choroquine treated cells | IRE1α/XBP1 and CHOP | [229] |
| Safrole | 5144 | AML (HL-60) | Terminal: apoptosis induction (assumed) | ATF6α, CHOP | [230] | ||
| Clofibrate | 2796 | peroxisome proliferator-activated receptor (PPAR) alpha | T-ALL | Terminal: apoptosis induction (assumed) | ASAPK/JNK | [231] | |
| Abnobaviscum F ® | Mitletoe aqueous extract | 135343633 | n.d. | CML | Terminal: contribution to the induction of cell death in treated cells (assumed) | GRP78/Bip, CHOP | [232] |
| MJ-29 | Quinazolinone | - | n.d. | murine myelomonocytic leukemia | Terminal: apoptosis induction | GRP78/Bip, CHOP, PERK | [233] |
| Imatinib (STI571) | 5291 | BCR-ABL tyrosine kinase | Terminal: apoptosis induction | not well documented | [234] | ||
| glycyrrhizic acid | 14982 | n.d. | murine myelomonocytic leukemia | Terminal: contributes to the induction of cell death in treated cells | GRP78/Bip, CHOP | [235] | |
| Gypenosides | - | n.d | HL-60 AML cell line | Terminal: apoptosis induction | ATF6α and ATF4 | [236] | |
| AICAr (+ methotrexate) | 5-aminoimidazole-4-carboxamide (AICA) riboside | 266934 | n.d | Nalm6 and CCRF-CEM cell lines (ALL) | Terminal: apoptosis induction | CHOP (C/EPB homologous protein) | [237] |
| Emodin | 6-methyl-1,3,8-trihydroxyanthraquinone | 3220 | n.d. | WEHI-3 murine myelomonocytic leukemia cell line | Terminal: apoptosis induction (assumed) | n.d. | [238] |
| Syrbactin | azamacrocyclic product | - | proteasome (26S) | REH ALL cell line | Terminal: apoptosis induction | CHOP (C/EPB homologous protein) | [239] |
| ABT-737 and GX15-070 | BH3 mimetics | 11228183/46930997 | BCL2 family proteins | Jurkat, NB4 and K562 cell lines | Terminal: Cytotoxic UPR | ATF4, ATF3, CHOP and NOXA, | [240] |
| NPB001-05 | n.d. | - | BCR-ABL | K562 cell line | Terminal: apoptosis induction (assumed) | not well documented | [241] |
| Ras inhibitor farnesylthiosalicylic acid (FTS, Salirasib) | 2-[[(2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl]thio]-benzamide | 5469318 | RAS | K562 cell line | Terminal: Cytotoxic UPR | not well documented | [242] |
| PYZD-4409 | 3,5-dioxopyrazolidine compound, 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furyl)methylene]-3,5-pyrazolidinedione | 60111983 | ubiquitin-activating enzyme UBA1 | K562, NB4, THP1, and U937 cell lines and AML primary leukemic cells | Terminal: apoptosis induction | PERK, CHOP, ATF4 | [243] |
| Korbazol | n.d. | - | n.d. | CLL primary leukemic cells | Terminal: apoptosis induction (assumed) | n.d. | [244] |
| Polymethoxyflavone tangeretin (TAN) | Flavonoids | - | n.d. | K562 cell line | Terminal: apoptosis induction | IRE1α, PERK, CHOP | [245] |
| Shiga toxine type 1 (Stx1) | n.d. | - | ribosomes (protein synthesis) | THP-1 cell line | Terminal: apoptosis induction | CHOP, TNF-related apoptosis-inducing ligand (TRAIL), DR5 and calpain | [246] |
| Eicosapentaenoic acid | 446284 | n.d. | HL60 (AML or APL) | Terminal: apoptosis induction (assumed) | PERK | [247] | |
| Xanthohumol | prenylated chalcone | 639665 | n.d. | CLL (patient samples) | Terminal: apoptosis induction | PERK, CHOP | [248] |
| Tunicamycin (UPR inducer) | 11104835 | N-acetylglucosamine phophotransferase | AML (U937 and HL60) | Terminal: cytotoxic through induction of lysosomal apoptotic pathway | GRP78/Bip, CHOP | [249] | |
| arsenic sulfide | [As4S4 (AS)] | 61569 | n.d. | BCR/ABL-positive K562 cell line | Terminal: apoptosis induction | not well documented | [250] |
| Fenretinide | synthetic retinoid derivative (related to vitamin A) | 5288209 | n.d. | NB4, U937 and HL60 cell lines | Terminal: apoptosis induction | PERK/eIF2α-CHOP (C/EPB homologous protein) | [251,252] |
| PABA/NO | O2-[2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl]1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate | - | PDI | HL60 cell line | Terminal: Cytotoxic UPR | CHOP (C/EPB homologous protein) | [253] |
| alkyl gallate and gallamide derivatives | - | n.d. | HL60 cell line | Terminal: apoptosis induction | not well documented | [254] | |
| Trichosanthin | type I ribosome-inactivating protein | 596174 | Ribosomes | HL60 cell line | Terminal: apoptosis induction | CHOP (C/EPB homologous protein) | [255] |
| auraptene | monoterpene coumarin ether | 1550607 | n.d. | Jurkat cell line | Terminal: apoptosis induction | Caspase 8 | [256] |
| 4-hydroxybenzylretinone | fenretinide analogue/synthetic retinoid derivative (related to vitamin A) | - | n.d. | HL60 cell line | Terminal: Cytotoxic UPR | CHOP (C/EPB homologous protein) | [257] |
| tipifarnib combined with bortezomib | quinolone and boronic acid | 159324/387447 | Farnesyltransferase Inhibiteur and 26 s proteasome inhibitor | KG-1, and U937 cell lines | Terminal: Cytotoxic UPR | not well documented | [258] |
| AEBSF | 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride | 186136 | serine protease inhibitor | NB4 cel line | Terminal: Cytotoxic UPR | not well documented | [259] |
| Thapsigargin (UPR inducer) | sesquiterpene lactone | 446378 | sarco/endoplasmic reticulum Ca++ ATPase | K562 cell line | Terminal: apoptosis induction | not well documented | [260,261] |
| arsenic trioxide (ATO) + kinase inhibitor imatinib mesylate (STI571) | 14888/5291 | BCR-ABL tyrosine kinase | K562 cell line and CML primary leukemic cells | Terminal: apoptosis induction | not well documented | [262] | |
| Tetrocarcin-A | 54681516 | n.d. | CLL/T-ALL | Terminal: apoptosis induction | not well documented | [263,264] |