Abstract
Accumulating evidence has indicated that corosolic acid exerts anti-diabetic, anti-obesity, anti-inflammatory, anti-hyperlipidemic and anti-viral effects. More importantly, corosolic acid has recently attracted much attention due to its anticancer properties and innocuous effects on normal cells. Furthermore, the increasing proportion of obese and/or diabetic populations has led to an epidemic of non-alcoholic fatty liver disease (NAFLD), which frequently progresses to hepatocellular carcinoma (HCC). Evidence has indicated that NAFLD is closely associated with the development of HCC and comprises a high risk factor. The present review summarizes the anticancer effects of corosolic acid in vitro and in vivo, and its related molecular mechanisms. It also describes the inhibitory effects of corosolic acid on the progression of NAFLD and its associated molecular mechanisms, providing guidance for future research on corosolic acid in NAFLD-related HCC prevention and treatment. To the best of our knowledge, a review of corosolic acid as an anticancer agent has not yet been reported. Due to its multitargeted activity in cancer cells, corosolic acid exerts anticancer effects when administered alone, and acts synergistically when administered with chemotherapeutic drugs, even in drug-resistant cells. In addition, as a novel tool to treat metabolic syndromes, corosolic acid uses the same mechanism in its action against cancer as that used in the progression of NAFLD-related HCC. Therefore, corosolic acid has been suggested as an agent for the prevention and treatment of NAFLD-related HCC.
Highlights
ZHAO et al: ANTICANCER ROLE OF COROSOLIC ACID and neurotoxicity, are major obstacles that cause treatment failure [10,11]
The cytotoxic effects of betulinic acid were subsequently confirmed in other cell lines, such as those derived from breast [23], colon and lung cancer [24], as well as neuroblastoma [25]
Corosolic acid at a concentration of 0.25‐32 μM for 3 or 5 days inhibited the proliferation of TRAMP‐C1 cells, a type of anchorage‐independent human prostate cancer (PCa) cell line with increased levels of mRNA and protein expression of nuclear factor erythroid 2‐related factor 2 (Nrf2), heme oxygenase‐1 (HO‐1) and nicotinamide adenine dinucleotide phosphate quinone oxido‐ reductase 1; corosolic acid did not exert the same inhibitory effect in Nrf2‐knockout TRAMP‐C1 cells [54]. These findings indicate that the significant cytotoxic effect of corosolic acid might be associated with its ability to restore the expression of Nrf2 via epigenetic modification [54]
Summary
Effects and mechanisms of corosolic acid in neoplasic cell lines from the digestive system. NA, not applicable; HER2, human epidermal growth factor receptor 2; AMPK, adenosine monophosphate; mTOR, activated protein kinase‐mammalian target of rapamycin; CCL‐2, chemokine (C‐C motif) ligand 2; Fas, apoptosis antigen 1; VEGFR, vascular growth factor receptor; Src, steroid receptor coactivator; FAK, focal adhesion kinase; cdc, cell division cycle; Smac, second mitochondria derived activator of caspase; Bax, B‐cell lymphoma‐2 associated X; NF‐κB, nuclear factor kappa‐B; IκBα, inhibitor of NF‐κBα; ER, endoplasmic reticulum; IRE‐1, inositol‐requiring ER‐to‐nucleus signal kinase 1; ASK1, apoptosis signal regulating kinase 1; JNK, Jun N‐terminal kinase; PERK, protein kinase RNA‐like ER kinase; eIF2α, eukaryotic initiation factor 2α; ATF4, activating transcription factor 4; CHOP, C/EBP‐homologous protein; p27Kip, cyclin‐dependent kinase inhibitor 1B; MELK, maternal embryonic leucine‐zipper kinase; FoxM1, forkhead box M1; Nrf, nuclear factor erythroid 2‐related factor 2; HO‐1, heme oxygenase‐1; STAT3, signal transducer and activator of transcription 3; MDSCs, myeloid‐derived suppressor cells; COX‐2, cyclooxygenase‐2; Akt, protein kinase B; ERK, extracellular signal‐regulated protein kinase; YAP, Yes‐associated protein; FasL, TNF ligand superfamily member 6; P65, NF‐кB subunit; 5‐Fu, 5‐Fluorouracil; TS, thymidine synthase; Bim, Bcl‐2 interacting mediator of cell death; PARP, poly ADP‐ribose polymerase; Bid, BH3 interacting domain death agonist; ROS, reactive oxygen species; H3KK27ac, lysine H3K27 acetylation; DNMTs, DNA methyltransferases; HDACs, histone deacetylases; H3K27me, trimethylation of lysine 27 on histone 3; PTX, paclitaxel; CDDP, Cisplatin; DOX, doxorubicin; ↑, indicates upregulation; ↓, indicates downregulation. The report established a promising therapeutic target of human retinoblastoma via MELK‐FoxM1 signaling (Table II) [101]
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