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Table 2 Mitochondria-targeted chemotherapeutics (mitocans) in synergistic combinations against AML

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 [3, 214]
Pediatric AML Phase I (NCT02676323)
de novo AML Phase II [215]
 1.4 Etoposide + mitoxanthrone mtDNA R/R AML   Phase II [216] [217];
 1.5.1 MEC (mitoxanthrone, etoposide, and cytarabine) + sirolimus mtDNA, mTOR R/R AML or secondary AML [218, 219] 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 [13, 34]
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 [86, 225, 226] 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 [21, 68]
 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 [35, 67]
 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] Phase II (NCT00184054) [113, 248];
 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.   Phase I/II [251]; phase III (NCT00513305) [252];
 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 [255, 256] 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 [223, 262]
 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 [267, 268]
 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 [272, 273]
 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 [280,281,282]
 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]