Cardamonin as a potential anticancer agent: Preclinical insights and clinical implications

Table 2 The in vivo animal-based anticancer activity of cardamonin

Cancer type	Model	Cancer induction	Dosage	Mechanism	Ref.
Liver	Athymic nude mice	HepG2-xenograft	Single oral daily of 25 mg/kg or 50 mg/kg for 24 days	Deactivated NF-κB signalling pathway by downregulating protein expression of PCNA, Ki-67 NF-κB-p65 and Ikkβ	[29]
Breast	BALB/c female mic	4T1-pcDNA3-TSP50-luc -xenograft	Single IP dose of 100 μg/50 μL every-three-days for 15 days	Inhibited overexpression of endogenous TSP50	[35]
	Athymic nude mice	SUM190-xenograft	Single IP dose of 25 mg/kg every-other-day for 17 days with doxorubicin	Abolished doxorubicin-enriched CSCs through downregulating mRNA expression of CSCs-associated genes (ALDH1, SOX2, OCT4, NANOG)	[38]
	Athymic nude mice	SUM190 and SUM149-xenograft	Single IP dose of 30 mg/kg every-other-day for 20 days	Blocked TLR3 on the induced-tumorigenic cancer stem cells	[27]
	Female nude mice	MDA-MB-231 cells xenograft	Single daily IP dose of 3 mg/kg for 28 days	Suppressed HIF-1α mediated-cell metabolism	[32]
	Female nude mice	MDA-MB-231 cells xenograft	Single IP dose of 30 mg/kg every-other-day for 28 days	Inducing apoptosis by upregulating expression of p21, p27, and Bim, and increasing the level of cleaved caspase 3, while cyclin D1 level decreased; activated FOXO3a-JNK signalling pathway by upregulating expressions of JNK and FOXO3a	[33]
	BALB/c mic	4T1-xenograft	Single oral daily dose of 5 mg/kg for 30 days	Retarded tumour growth (no further mechanistic information)	[37]
Colorectal	BALB/c nude mice	HT29-xenograft	Single IP dose of 25 mg/kg every-two-days per week for 28 days	Hindered metastasis to lungs by downregulating expression of ADRB2 and matrix metalloproteases (MMP-2 and MMP-9 N-cadherin)	[56]
	C57BL/6 mice	Azoxymethane-induced	Single oral daily dose of 40 mg/kg every-other-day for 90 days	Downregulated expression Ki67; deactivated STAT signaling pathway by downregulating protein expression of JAK2, STAT1, STAT3 and STAT5	[60]
	C57Bl/6 mice	Azoxymethane-induced	Single oral dose of 10 mg/kg five days per week for 30 weeks	Stopped colorectal cancer cells proliferation by downregulating Ki-67 index; deactivated Wnt/β-catenin and NF-κB signaling pathways; modulated expression of microRNAs	[53]
	C57Bl/6 mice	Azoxymethane-induced	Single oral dose of 10 mg/kg either from day 1 to day 140 or from day 50 to day 140	Reduced risk of colitis-induced colon cancer by reducing tumors number, increasing colon shrinkage and alleviating inflammatory insult; blocked accumulation of immune cells; deactivated NF-κB and iNOS signalling pathways; protected mice against inflammation-associated colitis by modulating expression of microRNAs	[59]
Lung (LLC cell)	C57BL/6 mice	LLC-xenograft	Single daily IP dose of 3.5 mg/kg, 7 mg/kg, or 10.5 mg/kg for 20 days	Reduced tumour size; hindered metastasis through inhibiting lung colonization of LLC cells	[71]
Lung (NSCLC)	BALB/c nude mice	H460-xenograft	Single daily IP dose of 5 mg/kg for 14 days	Downregulated expression of Ki-67 in lungs, and deactivated PI3K/Akt/mTOR signalling pathway by downregulating protein expression of Akt and mTOR	[64]
Gastric (5-FU-resistan)	BALB/c nude mice	BGC-823/5-FU xenograft	Single IP dose of 25 mg/kg twice per week for 30 days	Superior retarding tumour growth (no further mechanistic information)	[73]
Esophageal cancer	Male nude mice	EC9706 xenograft	Single oral dose of 5 mg/kg, 15 mg/kg, or 25 mg/kg every-three-days for 26 days	Downregulated protein expression of PCNA, BCL-2, vimentin, PI3K, and Akt; deactivated mTOR signalling pathway	[30]
Pancreas	Athymic BALB/c nude mice	PANC-1 and SW1990 xenograft	Single daily IP dose of 5 μg/kg for 42 days	Modulating FOXO3a/FOXM1 axis pathway through upregulating expression of FOXO3a; deactivated FOXM1/AKT/mTOR signalling pathway by lowering phosphorylation of PI3K, AKT, and mTOR	[63]
Ovarian	Female BALB/c nude mic	SKOV3 or a mix of SKOV3 and M2 macrophages xenograft	Single daily IP dose of 5 mg/kg or 25 mg/kg for 15 days	Downregulated protein expression of Ki67, CD163 and CD206; deactivated mTOR signalling pathway	[39]
	BALB/c nude mice	SKOV3 and PDC xenograft	Single daily IP dose of 20 mg/kg for 13 days	Induced apoptosis; deactivated mTOR and NF-κB signaling pathways	[43]
	Female BALB/c nude mice	SKOV3 xenograft	Single oral daily dose of 15 mg/kg or 30 mg/kg for 20 days	Downregulated expression of Ki-67, raptor and FASN, activated mTOR signaling pathway	[42]
Leukemia	Male BALB/c mice	WEHI-3 xenograft	5 mg/kg, IP, once every two days for 14 days and 42 days	Improved animal survival after 42 days, decreased population of CD3 (T cells), CD11b (monocytes) and macrophages-3 after 14 days, increased population of CD19 (B cells), and enhanced macrophages phagocytic ability	[68]
Lymphoma	Female SCID mice	SUDHL-4 cells expressing mutant; RRAGC xenograft	Single oral daily dose of 15 mg/kg for 30 days	Sensitized RagCT90N-mutant highly to cardamonin	[65]
Osteosarcoma	Female BALB/c nude mice	143B xenograft	Single oral dose of 5 mg/kg, 15 mg/kg, or 25 mg/kg every-two-days for 20 days	Deactivated mTOR signalling pathway, inhibited level of PCNA, BCL-2 and vimentin, and increased phosphorylation level of p38 MAPK and JNK	[31]

NSCLC: Non-small-cell lung cancer; 5-FU: 5-fluorouracil; TSP: Testes-specific protease; IP: Intraperitoneal injection; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; PCNA: Proliferating cell nuclear antigen; IKK: Inhibitor of nuclear factor kappa-B kinase; CSCs: Cancer stem cells; ALDH1: Aldehyde dehydrogenase 1; SOX2: SRY-box transcription factor 2; OCT4: Octamer binding transcription factor 4; TLR3: Toll-like receptor 3; HIF-1: Hypoxia-inducible factor; FOXO3a: Forkhead box O3a; JNK: C-Jun N-terminal kinase; ADRB2: Adrenoreceptor beta 2; MMP: Matrix metalloproteinase; STAT: Signal transducer and activator of transcription; JAK: Janus kinase; iNOS: Inducible nitric oxide synthase; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; BCL-2: B cell lymphoma 2; FOXM1: Forkhead box M1; CD: Cluster of differentiation; FASN: Fatty acid synthase; RagC: Ras-related guanosine triphosphate-binding protein C; p38 MAPK: P38 mitogen-activated protein kinase.