Table 1.

List of AKR1B1‐related drugs and their effects in vitro and in vivo experiments

Drug name	Experiment status	Description	Ref.
Epalrestat	in vivo	The only FDA approved AKR1B1 inhibitor The only AKR1B1 inhibitor approved in Japan Phase II clinical trial in China on triple‐negative breast cancer	89, 105, 106
Epalrestat	in vitro (MDA‐MB231 and SUM159)	restored E‐cadherin expression suppressed invasion and migration reduced PGF2a synthesis, the formation of tumour spheres and the frequency of colonies	51
	in vivo (female SCID mice)	decreased the size of tumours suppressed lung tumour metastasis
Epalrestat	in vitro (MDA‐MB‐231 and 4T1)	targeted co‐delivery of Epalrestat and Doxorubicin via a redox‐sensitive pro drug increased apoptosis increased stoppage of the cell cycle in the G2/M phase	101
Fidarestat	in vivo (ApcMin/+ mice)	decreased the number of polyps induced by high fat diet (HFD) abrogated the HFD induced expression of PCNA, β‐catenin and phospho‐NF‐κB P65 decreased Cox‐2, iNOS decreased AKT activation and increase PKC B2	38
Fidarestat	in vitro (HT29)	decreased COX‐2, iNOS, XIAP, survivin, β‐catenin and NF‐κB	39
	in vivo (male C57BL/KsJ‐db/db mice treated with AOM)	inhibited PKC‐β2, AKT, COX‐2 and iNOS
Fidarastat	in vitro ( HT29)	down‐regulated Bcl‐xL, Bcl‐2, survivin, XIAP and FLIP to up‐regulated pro‐apoptotic proteins such as BAX led to release of cytochrome c and activation of caspases‐3 increased death receptors DR5 and DR4, thus, increased TRAIL‐induced cytotoxicity and induced apoptosis regulated AKT/PI3K through activation of forkhead transcription factor FOXO3a	45
Fidarastat	in vitro & in vivo	increased the cells responsiveness to oxidative stress decreased mitochondrial DNA damage suppressed tumour cells increased Nrf2 (synergy with EGF) increased the Nrf‐2 DNA binding activity and decreased Keap‐1 expression enhanced the activity of Nrf2 stimulated by EGF in vitro & in vivo, thus, helped the cells adapt to oxidative stress enhanced the mitochondrial biogenesis under oxidative stress PCG‐1α, Nrf1 and TFAM were up‐regulated	47, 107
Fidarastat	in vitro	increased AMP‐protein kinase (AMPK) phosphorylation decreased the phosphorylation of mTOR in SW480 increased the expression of p53	47, 107
Fidarestat	in vitro (HT‐29 & SW480) and in vivo	increase the sensitivity to DOX and its accumulation decreased MDR1, MRP1 and ABCG2 inhibited DOX adverse effects could be used as adjuvant therapy to enhance DOX efficacy	100
Fidarestat	in vitro (HUVEC)	reduced endothelial cell death induced by DOX prevented the oxidative stress and ROS formed by DOX induction abrogated the effect of DOX on the induction of the expression of ICAM‐1 and VCAM‐1 as well as the adhesion of monocytes restored nitric oxide (NO)‐levels and eNOS expression decreased by DOX soothed the activation of inflammatory responses such as NFκB and cytokines in HUVECs and in vivo prevented the cardiac hypertrophy and expression of eNOS, iNOS and 3‐Nitrotyrosine in tissues of the aorta averted cytotoxicity created by DOX in non‐cancerous tissues	108
Fidarestat	in vitro (HUVEC) & in vivo (Fischer 344 rats)	inhibited angiogenesis factors such as Ki67 inhibited invasion and migration induced by VEGF‐ and FGF hindered MMP2 and MMP9 as well as ICAM, VCAM prevented the secretion of ICAM, VCAM, MMP2, MMP9 and IL‐6 induced by VEGF‐ and FGF into culture media increased IFN‐γ reduced proliferation prevented pi3k activation, phosphorylation of AKT, activation of NFκB and protein‐HNE adducts induced by VEGF hindered migration, invasion and creation of cells into structures like capillary in rats led to decreased expression of CD31 and vWF	109
Gedunin (compound)	SCC131 (Oral Cancer) and Eahy926)	inhibited AKR1B1 expression, ROS formation and hypoxia‐induced cell migration inactivated Akt, ERK and NFκB better anti‐cancer effects alongside Epalrestat treatment	110
Gedunin	in vivo (Syrian hamsters)	inactivated Akt and inhibitory kappa B kinase (IKK) inhibited PI3K/Akt and NF‐κB pathways suppressed hamster buccal pouch (HBP) carcinomas progression inhibited mir‐21 vascular endothelial growth factor and hypoxia inducible factor‐1 alpha (HIF‐1α)	111
Aglycone extract of Genistein	in vitro MDA‐231	down‐regulated AKR1B1	112
Extract of artichoke leaves (bracts)	in vitro (human monocytic leukaemia cell line THP‐1)	inhibited AKR1B1 and NFκB activity in human leukaemic monocytes diminished the expression of COX‐2 and MMP‐2	113
Vincristine and 5‐aza‐dC	in vitro	could not affect AKR1B1 methylation but induced its expression in CRC	81
UPA (Ulipristal acetate)	In vitro	induced AKR1B1 expression slightly in myometrial cells decreased AKR1B1 expression in leiomyoma cells	114