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

 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]

–

 2.1

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]

–

 3.1

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]

–

 4.1.1

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)

 5.1

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]

–

 6.1.1

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]

–

 7.1

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]

–