Table 2 Therapeutic agents for blocking mito-nuclear communication in CSCs

Mitochondrial energy metabolism

Oxidative phosphorylation, mitochondrial complex I

Metformin, mitochondrial complex I inhibitor

Downregulates the expression of CSC-related genes, decreases the ratios of CD44^highALDH^high cells as well as the sizes and numbers of tumorspheres, reduces the volume of tumors

sphere enriched CSCs in cholangiocarcinoma [116]; HNSCC CSCs [117]

Methionine cycle, SAM levels

FIDAS-5, MAT2A inhibitor

Inhibits the expression of methylation marks of H3K4me3 etc., reduces the mass and volume of xenograft tumors, diminishes the size of NOD.Cg-Prkdc^scid Il2rgtm1^Wjl/SzJ mouse lung lesions, decreases the ratio of CD166⁺ CSCs

sphere enriched and CD166⁺ Lung CSCs [118]

Cycloleucine, MAT2A inhibitor

Suppresses the demethylation of H3K4me3 and inhibits the protein expression of the stemness transcription factor SOX9; the combination of cycloleucine and methionine depletion more effectively reduces mammospheres in vitro and the burden of primary and lung metastases in vivo

sphere enriched BCSCs [119]

Mitochondrial dynamics

Mitochondrial fission

Mdivi-1, DRP1 inhibitor

Reduces the percentages of SP⁺ and CD44⁺ CSC subpopulations, inhibits the expression of stemness genes, suppresses the formation capacity of tumorspheres in vitro and tumors in vivo, and decreases the ability of self-renewal

LCSCs [91]; NPC CSCs [120]; Ovarian CSCs and Colorectal CSCs [121]; Pancreatic CSCs [86]; CD133⁺CD15⁺BTICs [92]; EpCAM⁺CD133⁺ LCSCs [91]

Resveratrol, etodolac, celecoxib; selective COX-2 inhibitor

Reduces the expression levels of the stemness genes, the ratio of SP⁺ subpopulations, and the capacity for tumorsphere formation

NPC CSCs [120]; Bladder CSCs [122]; Glioblastoma CSCs [123];

MFF

OTX015, BRD4 inhibitor

Suppresses tumorigenicity and self-renewal ability

Prostate CSCs [112]

Furamidine, PRMT1 inhibitor

Blocks TBX19-induced mitochondrial fission, and decreases the capacity of tumorsphere formation and tumorigenesis

LCSCs [91]

Mitochondrial homeostasis

Mitochondrial mitophagy

Combination of melatonin and verteporfin, PINK1/parkin signa

lling pathway inhibitor

Reduces the capacity of tumorsphere formation and the numbers of CD44⁺CD24⁻ and CD133⁺ CSCs

HNSCC CSCs [124]

Mefloquine hydrochloride, lysosomes RAB5/7 inhibitor

Decreases the ratio of CD44v9⁺/CD133⁺ colon CSCs

CD44v9⁺/CD133⁺ Colon CSCs [125]

¹⁸⁸Re-liposome, nanomedicine, lysosomal proteins inhibitor

Reduces the protein levels of (Lamp-1 and cathepsin-B) and autophagy/mitophagy (LC3B, Atg16 L and Becline-1) markers, decreases tumor growth in xenograft mouse models, lowers CA-125 levels, and prolongs ovarian cancer patients’ survival in a clinical phase I trial

Ovarian CSCs [126, 127]

Mitochondrial biosynthesis

Azithromycin, doxycycline; Tigecycline, mitochondrial ribosome inhibitor

Targets the 39 s and 28 s mitochondrial ribosomes and inhibits tumorsphere formation, tumorigenicity and self-renewal ability

CSCs in breast, ovarian, lung, prostate, pancreatic cancer, melanoma, DCIS and GBM [128]; LSCs [129]

SR-18292, selective PGC-1α inhibitor

Reduces tumorsphere formation, shrinks tumor size, and downregulates the expression of genes involved in stemness maintenance and self-renewal

sphere enriched CSCs in cholangiocarcinoma [116]

XCT790, ERRα-PGC1 signaling pathway inhibitor

Inhibits the formation of mammospheres and decreases the proportion, survival and propagation of CD44⁺CD24⁻ BCSCs

BCSCs [100]

Mitochondrial ROS

Electron transport

Deferiprone, iron chelator

Decreases the proportions of tumorspheres and ALDH⁺ CSCs

BCSCs [130]

ROS-STAT3 signaling pathway

KS10076, metal chelator

Reduces the capacity for tumor formation, decreases the expression levels of CSC self-renewal genes, and decreases the ratios of subpopulations of ALDH⁺ or CD44^highCD24^low CSCs

Colon CSCs [131]

13 R, 20-diHDHA, dihydroxy-DHA derivative

Reduces the capacity for tumorsphere formation, decreases the expression levels of CSC self-renewal genes, and decreases the ratios of subpopulations of ALDH⁺ or CD44^highCD24^low BCSCs

sphere enriched BCSCs [132]

PAA, flower flavor

Reduces the capacity for tumorsphere formation and tumor formation, decreases the expression levels of CSC self-renewal genes, and decreases the ratios of subpopulations of ALDH⁺ or CD44⁺CD24⁻ CSCs

sphere enriched BCSCs [133]

ROS-AKT signaling pathway

TiOxNPs, titanium peroxide nanoparticles

Sensitizes radioresistant CSCs to ionizing radiation, decreases tumorsphere number and CSC marker expression levels, reduces the pancreatic CSC self-renewal ability, decreases tumor growth rate and necrosis area, and improves of mouse survival rate

sphere enriched Pancreatic CSCs [134]