Dicoumarol: from chemistry to antitumor benefits

Chinese Medicine

Table 2 Anticancer effects of dicoumarol assessed in vitro and in vivo

In vitro studies
	Cancer type	Cell line	Dicoumarol effects	Refs.
NQO1 inhibition-dependent actions	Pancreatic	MIA PaCa-2	↑ Apoptosis and oxidative stress via NQO1 inhibition ↑ Cytosolic cytochrome c and cleaved PARP ↑ Total glutathione and GSSG	[97]
	Colon	HCT116	↑ Miltirone-induced apoptosis and mitochondrial damage via ↓ p53 stability due to NQO1 deficiency ↑ Loss of mitochondrial mass ↓ Mitochondrial ROS	[98]
	Urogenital	RT112 253J LNCap	↑ Cisplatin cytotoxicity ↓ p53-p21 pathway ↑ JNK	[99]
	Urogenital	KK47	↑ Doxorubicin cytotoxicity ↓ p53-p21 pathway ↑ p38-MAPK activation ↑ Cleaved caspase-3 ↓ Mcl-1	[100]
NQO1 inhibition-independent actions	Breast	MCF-7	↓ Chemoresistance via PSG1-TGFβ1-EMT pathway ↓ PSG1 expression ↓ TGFβ1 activation ↓ N-cadherin, vimentin and fibronectin expression	[101]
	Renal	Caki	↑ TRAIL-mediated apoptosis ↑ Cleaved PARP ↓ Bcl-2, Mcl-1, and c-FLIP expression ↓ NF-κB and CRE transcriptional activity	[102]
	Myeloid leukemia	HL-60	↑ Superoxide release Inhibition of OXPHOS complexes II, III and IV Inhibition pyrimidines biosynthesis	[91]
	Ovarian	SKOV3	↓ PDK1 kinase activity, aerobic glycolysis → OXPHOS, ↑ apoptosis, and ↓ cell viability ↓ p-PDHA1 ↑ Glucose uptake ↓ Lactate production ↑ Cleaved caspase-3, cleaved PARP ↑ ROS ↓ Mitochondrial membrane potential	[103]

In vivo studies
	Cancer type	Animal model	Dicoumarol effects	Refs.
NQO1 inhibition-dependent actions	Pancreatic	MIA PaCa-2 xenografts (athymic nude mice)	↓ Tumor volume growth ↑ Animals’ survival	[97]
NQO1 inhibition-independent actions	Ovarian	SKOV3 xenografts (BALB/c-nu mice)	Inhibition of PDK1 activity and ↑ apoptosis ↓ p-PDHA1 ↑ Cleaved caspase-3 and cleaved PARP ↑ TUNEL⁺ cells ↓ Tumor volume and weight	[103]

5-FU 5-fluorouracil, c-FLIP cellular FLICE-like inhibitory protein, CRE cyclic adenose monophosphate response elements, EMT epithelial–mesenchymal transition, GSSG glutathione disulfide, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, NF-κB nuclear factor kappa B, NQO1 NAD(P):(quinone acceptor) oxidoreductase 1, OXPHOS oxidative phosphorylation, PARP poly (adenosine diphosphate-ribose) polymerase, PDHA1 pyruvate dehydrogenase E1 component subunit alpha, PDK1 phosphoinositide-dependent kinase-1, PSG1 pregnancy specific beta-1-glycoprotein 1, ROS reactive oxygen species, TRAIL tumor necrosis factor-related apoptosis-inducing ligand, TGFβ1 transforming growth factor beta 1, TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling

ISSN: 1749-8546