From: Mitochondrial metabolism as a target for acute myeloid leukemia treatment
N | Drug combination | Targets/inhibition related to mitochondria | AML subgroup if applicable | Level 1: preclinical (in vitro, PDX) | Level 2: clinical trials/studies in AML patients |
---|---|---|---|---|---|
1. DNA-targeted combinations/cytotoxic chemotherapy | |||||
 1.1 | CPX-351, vyxeos (cytarabine + daunorubicin in liposomal encapsulation at 5:1 synergistic ratio) | mtDNA | AML with myelodysplasia-related changes; therapy-related AML. Can be used to treat elderly patients | [210] | Phase III [211] FDA-approved |
 1.2 | Etoposide + cytarabine + azacitidine | mtDNA | Elderly de novo AML patients | [212] | [213] |
 1.3 | Cytarabine/daunorubicin/idarubicin + HDACi (vorinostat, parabinostat, etc) | mtDNA | R/R AML | – | |
Pediatric AML | Phase I (NCT02676323) | ||||
de novo AML | Phase II [215] | ||||
 1.4 | Etoposide + mitoxanthrone | mtDNA | R/R AML |  | |
 1.5.1 | MEC (mitoxanthrone, etoposide, and cytarabine) + sirolimus | mtDNA, mTOR | R/R AML or secondary AML | Phase I [220] | |
 1.5.2 | Cytarabine (consolidation therapy) + everolimus | AML | [221] | ||
 1.5.3 | Low-dose cytarabine + everolimus | Elderly AML | Phase Ib [222] | ||
 1.5.4 | Cytarabine + daunorubicin + everolimus | Relapsed AML | Phase I (NCT00544999) | ||
 1.6 | Cytarabine + ibrutinib | mtDNA, NF-kB | AML | [223] | Phase IIa [224] |
 1.7 | Cytarabine + 2-DG | mtDNA, hexokinase II | AML | – | |
2. Combinations based on apoptosis induction (Bcl-2, Mcl1 inhibition) | |||||
 2.1 | Venetoclax + hypometylating agents (e.g., decitabine, azacitidine) | Bcl-2,OxPhos (complex II),amino acid uptake, Nrf2 pathway | De novo/relapsed AML | Phase Ib [227] FDA-approved | |
 2.2.1 | Venetoclax/obatoclax + FAO inhibitors (etomoxir, ranolazine) | Bcl-2, FAO (CPT1a), MPTP | AML | [21] | – |
 2.2.2 | Venetoclax + azacitidine + FAO inhibitors | [28] | |||
 2.3.1 | Venetoclax + low-dose cytarabine | Bcl-2, mtDNA | AML patients > 60 y.o. ineligible for induction chemotherapy | [228] | Phase Ib/II [229]; phase III (NCT03069352) FDA-approved |
 2.3.2 | Venetoclax + cytarabine +/- idarubicin | Pediatric R/R AML | Phase I [230] | ||
 2.3.3 | Venetoclax + cytarabine + daunorubicin; liposome-encapsulated | R/R AML; de novo AML | Phase II (NCT03629171) | ||
 2.4 | Venetoclax + FLT3-ITD inhibitor (quizartinib) | Bcl-2 | AML with FL3-ITD mutation | [231] | Phase Ib/II (NCT03735875) |
 2.5 | Venetoclax + IDH2 mutant inhibitor (enasidenib) | Bcl-2, citric acid cycle | AML with IDH2 mutation R/R AML | [232] | Phase Ib/II (NCT04092179) |
 2.6.1 | Venetoclax + tedizolid | Bcl-2, mitochondrial protein synthesis, OxPhos | AML | [142] | – |
 2.6.2 | Venetoclax + azacitidine + tedizolide | ||||
 2.7 | Obatoclax + 2-DG | Bcl-2, hexokinase II | AML | [34] | – |
 2.8 | S63845 + S55746 | Mcl1, Bcl-2 | AML | [233] | – |
 2.9.1 | S63845 + daunorubicin | Mcl1, mtDNA | MLL-AF9 AML | [234] | – |
 2.9.2 | S63845 + venetoclax | Mcl1, Bcl-2 | |||
 2.10.1 | A-1210477 + venetoclax | Mcl1, Bcl-2 | AML | [140] | – |
 2.10.2 | UNBS1450 + venetoclax | [235] | |||
 2.11 | AZD5991 + venetoclax | Mcl1, Bcl-2 | AML | [183] | Phase I/II (NCT03218683) |
 2.12 | Obatoclax + HDACi | Bcl-2,autophagy induction | AML | [236] | – |
3. Combinations targeting mitochondrial metabolism | |||||
 3.1 | CPI-613 + mitoxanthrone + high-dose cytarabine | PDK, mtDNA | R/R AML | [48] | Phase I [48] |
 3.2 | Telaglenastat + venetoclax | Glutaminase, Bcl-2 | AML | [59] | – |
 3.3.1 | Telaglenastat + arsenic trioxide | Glutaminase, ROS production, MMP | AML | [61] | – |
 3.3.2 | Telaglenastat + homoharringtonine | ||||
 3.4 | Telaglenastat + azacitidine | Glutaminase | AML | [237] | Phase I (NCT02071927) |
 3.5 | Telaglenastat + AC220 (FLT3 inhibitor) | Glutaminase, ROS production | FLT3-mutated AML | [238] | – |
 3.6.1 | ADI-PEG 20 (pegylated arginase) + cytarabine | Arginine depletion, mtDNA | AML | [193] | Phase I (NCT02875093) |
 3.6.2 | BCT-100 (pegylated arginase) + cytarabine | [194] | – | ||
 3.7.1 | Asparaginase + low/high-dose cytarabine | Asparagine depletion, mtDNA | R/R AML/Elderly AML patients > 65 y.o. |  | Phase II (NCT01810705) [239]; |
 3.7.2 | Asparaginase + high-dose cytarabine + mitoxanthrone | [240] | |||
 3.8 | Etomoxir (FAO inhibitor) + cytarabine | CPT1a, MPTP, mtDNA | AML | – | |
 3.9.1 | Etomoxir + arsenic trioxide | CPT1a, MPTP, ROS production | AML, APL | [241] | – |
 3.9.2 | Etomoxir + arsenic trioxide + 2-DG/lonidamine | CPT1a, MPTP, ROS production, Hexokinase II | |||
 3.10 | Avocatin B + cytarabine | FAO, ROS production, mtDNA | AML | [242] | – |
4. Combinations targeting OxPhos | |||||
 4.1.1 | Metformin + 2-DG | Complex I, hexokinase II | AML | [79] | – |
 4.1.2 | IACS-010759 + 2-DG | [35] | – | ||
 4.1.3 | Rotenone + 2-DG | ||||
 4.2 | Metformin + sorafenib | Complex I, mTOR | FLT3-mutated AML | [243] | – |
 4.3 | Metformin + 6-BT | Complex I, STAT5, glycolysis | FLT3-mutated AML | [244] | – |
 4.4 | Metformin + cytarabine | Complex I, mTOR, mtDNA | R/R AML | [245] | Phase I (NCT01849276) |
 4.5 | Metformin + NSAIDs (diflunisal + diclofenac) | Complex I | AML | [80] | – |
 4.6 | CCCP + 2-DG | MMP, hexokinase II | AML | – | |
 4.7 | IACS-010759 + vinorelbine | Complex I, OxPhos | AML | [35] | – |
 4.8 | IACS-010759 + doxorubicin + cytarabine | Complex I, mtDNA | AML | [246] | – |
 4.9 | Antimycin + 3-BrOP | Complex III, glycolysis, ATP depletion | AML | [87] | – |
 4.10 | Oligomycin + tyrosine kinase inhibitors | Complex V, ROS production | FLT3-mutated AML | [89] | – |
 4.11 | Isobavachalcone + doxorubicin | DHODH, mtDNA | AML | [199] | – |
 4.12 | ASLAN003 + azacitidine | DHODH | AML patients > 60 y.o. |  | Phase II (NCT03451084) |
5. Combinations inducing ROS generation/targeting mitochondrial membrane complexes | |||||
 5.1 | Diamide + doxorubicin | UCP2, mtDNA | AML | [247] | – |
 5.2 | Arsenic trioxide + high-dose ascorbate | ANT, MMP,ROS production | APL (more promising results than in AML) | [112] | |
 5.3.1 | Arsenic trioxide + decitabine/azacitidine | ANT, MMP,ROS production | AML | [249] | Phase II (NCT02190695) |
 5.3.2 | Arsenic trioxide + decitabine/azacitidine + ascorbate | Phase I [250] | |||
 5.4.1 | Arsenic trioxide + low-dose cytarabine | ANT, MMP, ROS production, mtDNA | AML patients > 60 y.o. |  | |
 5.4.2 | Arsenic trioxide + high-dose cytarabine + idarubicin | AML patients < 60 y.o. | Phase I [253] | ||
 5.5 | Arsenic trioxide + mTOR inhibitors (rapamycin) | ANT, MMP, ROS production, mTOR | AML lacking t(15;17) translocation (non-APL) | [254] | – |
 5.6 | Arsenic trioxide + proteasome inhibitor bortezomib | ANT, MMP, ROS production, NF-kB, UPR activation | AML, APL/relapsed APL | Phase II [257] | |
 5.7.1 | Arsenic trioxide + lonidamine | ANT, MMP, ROS production, mTOR, glycolysis | AML | [258] | – |
 5.7.2 | Arsenic trioxide + 3-BP | ANT, MMP, ROS production, glycolysis | AML | [186] | – |
5.8 | Arsenic trioxide + DCA | ANT, MMP, ROS production, PDK, Mcl1 | AML, including FLT3-ITD, R/R AML | [259] | [259] |
 5.9 | Arsenic trioxide + ATRA | ANT, MMP, ROS production | APL | [260] | Phase III [261] |
 5.10 | Parthenolide + 2-DG+ temsirolimus | ROS production, Nrf2, PPP, mTOR, hexokinase II | AML | [116] | – |
 5.11.1 | Parthenolide + ibrutinib | ROS production, NF-kB, mtDNA | AML | – | |
 5.11.2 | Daunorubicin + ibrutinib | ||||
 5.12 | Triptolide + idarubicin | ROS production, Nrf2, HIF1α | AML | [263] | – |
 5.13 | Resveratrol + HDACi | ROS production, DNA damage | AML | [264] | – |
 5.14 | Cytarabine + PK11195 (PBR ligand) | mtDNA, MPTP | AML | [265] | – |
6. Combinations targeting autophagy/mitophagy | |||||
 6.1.1 | Bafilomycin A1 + cytarabine | Autophagy, ROS production, MMP, mtDNA | AML | [266] | – |
 6.1.2 | Chloroquine + cytarabine | ||||
 6.1.3 | Hydroxychloroquine + cytarabine | ||||
 6.2 | Hydroxychloroquine + mitoxanthrone + etoposide | Autophagy, mtDNA | R/R AML |  | Phase I (NCT02631252) |
 6.3 | Chloroquine + arginase | Autophagy, arginine depletion | AML | [269] | – |
 6.4 | Chloroquine + HDACi (valproic acid/ vorinostat) | Autophagy, accumulation of ubiquitinated proteins | t(8;21)-mutated AML | [270] | – |
 6.5 | ROC-325 + azacitidine | Autophagy | AML | [271] | – |
 6.6.1 | SBI-0206965 + cytarabine | ULK1 (autophagy), ROS production, DNA damage, mtDNA/Bcl-2 | AML | – | |
 6.6.2 | SBI-0206965 + venetoclax | ||||
 6.6.3 | SBI-0206965 + daunorubicin | [274] | |||
 6.7.1 | JQ1 + daunorubicin | BET-bromodomain proteins (S100A8/9, BRD4), mtDNA | AML | [275] | – |
 6.7.2 | JQ1 + cytarabine | [276] | |||
 6.8 | Birabresib + venetoclax | BET-bromodomain proteins, Bcl-2 | AML | [277] | – |
 6.9 | LCL-461 + FLT3-inhibitor crenolanib | Activation of ceramide-dependent mitophagy | AML with FL3-ITD mutation | [163] | – |
 6.10 | TAK-165 + FLT3-inhibitor AC220 | Autophagy | AML with FL3-ITD mutation | [278] | – |
 6.11 | Petromurin C + FLT3-inhibitor gilteritinib | Induction of early autophagy and apoptosis, Mcl1 | AML with FL3-ITD mutation | [279] | – |
7. Combinations targeting mitochondria-related miRNAs | |||||
 7.1 | miR-181a/b mimics + doxorubicin/daunorubicin/cytarabine | Mcl1, Bcl-2, mtDNA | AML | – | |
 7.2 | miR-15a/16-1 mimic + arsenic trioxide | UCP2, MMP, cytochrome c release, ROS production | AML | [283] | – |
 7.3 | miR-9 mimic + daunorubicin | EIF5A2, Mcl1, mtDNA | AML | [284] | – |
 7.4.1 | miR-29b mimic + cytarabine | Mcl1, mtDNA | AML | [285] | – |
 7.4.2 | miR-29b mimic + decitabine | [286] | |||
 7.5 | Antisense miR-32 + cytarabine | Bim upregulation, mtDNA | AML | [287] | – |