Anticancer Activities of Protopanaxadiol- and Protopanaxatriol-Type Ginsenosides and Their Metabolites

Table 1

Summary of the anticancer activities of PPD and PDS.

Compounds	Activities	Mechanisms
Protopanaxadiol (PPD)	Antiproliferation	G1 phase arrest; promotes melanin production and increases DNA binding sites on the cell surface and cell adhesiveness [69]; stimulates differentiation [31]; induces caspase-dependent apoptosis [70]; activates NF-κB signaling [71]; downregulates PI3K/Akt signaling pathway [50]
	Inhibit tumor growth	Suppresses NF-κB, JNK, and MAPK/ERK signaling pathways [48]; downregulates full-length AR expression and activity and its constitutively active splice variants [6]
	Antimetastasis	Downregulates MMP-9 [72] and MMP-2 [73]
	Antiangiogenesis	Inhibits the proliferation HUVECs
	Synergy and attenuation	Synergies with cyclophosphamide, mitoxantrone, 5-FU, docetaxel, epicatechin, paclitaxel or vinblastine, irinotecan, tamoxifen, or doxorubicin [74–76]. Reverses MDR and inhibits P-gp [77]
Ginsenoside Rg3	Antiproliferation	Induces calcium-dependent apoptosis and autophagy [78]; induces DNA double-strand breaks [79]; downregulates HIF-1α expression under hypoxia conditions [80]; downregulates PI3K/Akt [81] and three modules of MAP kinases [82]; inhibits COX-2, NF-κB, phosphorylation of STAT3, ERK1/2, and JNK [83]
	Active tumor suppressors	Induces senescence-like growth arrest by regulating Akt and p53/p21-dependent signaling pathways [61]
	Inhibit cellular metabolism	Increases the cellular GSH/GSSG ratio, enhances the γ-GCS activity, and suppresses ROS generation [84]
	Antiangiogenesis	Degrades serum IGF-1 level [85]; downregulates KDR and VEGF expressions [86]; decreases intratumoral microvessel density [87]; inhibits VEGF dependent p38/ERK signaling in vitro and inhibits the mobilization of endothelial progenitor cells from the bone marrow microenvironment to the peripheral circulation [88]
	Inhibit tumor growth	Downregulates Wnt/β-catenin signaling [54]; decreases HDAC3 and increases acetylation of p53 [63]; decreases FUT4/LeY expression and inhibits the activation of EGFR/MAPK pathway [89]
	Antimetastasis	Suppresses invasion and MMP-9 expression level [90]; inhibits micro-lymphatic metastasis of colorectal neoplasms [91]; blocks hypoxia-induced EMT, activates the ubiquitin-proteasome pathway to promote HIF-1α degradation, upregulates E-cadherin via transcriptional suppression of Snail, and downregulates vimentin under hypoxic conditions [92]
	Synergy and attenuation	Reverses P-gp-mediated MDR [93]; increases radiosensitivity [94]; synergies with 5-FU, As2O3 (arsenic trioxide), capecitabine, cisplatin, CTX, docetaxel, doxorubicin, gemcitabine, gemcitabine plus cisplatin, mitomycin C and tegafur, paclitaxel, ribonuclease inhibitor, suramin, tamoxifen, TRAIL, verapamil, and vinorelbine+cisplatin [95–100]
	Immunomodulation	Improves cellular immunity and stimulates ConA-induced lymphocyte proliferation and augmentation of Th1-type cytokines IL-2 and IFN-γ levels in mice [101]; improves the immune function [102]
	Prevent tumorigenesis	Reduces tumor incidence in N:GP(S) newborn mice injected with benzo(a)pyrene [103]; downregulates NF-κB and AP-1 [104]
Ginsenoside Rh2	Antiproliferation	G1 phase arrest [105]; induces cell differentiation and reduces telomerase activity [106]; induces Ca^2+-dependent mitochondrial apoptosis pathway [107]; induces autophagy [78]; activates NF-κB signaling pathway and upregulates TNF-α [108]; reduces Akt/mTOR signaling [109]
	Active tumor suppressors	Increases the expression level of DR4 death receptor [65]; upregulates miRNA-128 expression [110]; activates p53 [64]
	Inhibit cellular metabolism	Induces AMPK and p38 MAPK activation. AMPK determines apoptotic sensitivity of cancer cells to Rh2 [111]
	Inhibit tumor growth	Inhibits EGFR signaling through PI3K/Akt/mTOR signaling pathways [112] and upregulation of miR-491 [113]; augment of TGF-β receptor signaling [114]
	Antiangiogenesis	Inhibits angiogenesis and lymphangiogenesis and downregulates JAM expression [115]
	Synergy and attenuation	Synergies with cisplatin, betulinic acid, CTX, daunomycin, vinblastine, docetaxel, paclitaxel, and mitoxantrone [116, 117]; reverses P-gp-mediated MDR [118]
	Prevent tumorigenesis	Decreases the tumor incidence in N:GP(S) newborn mice injected with benzo(a)pyrene model [103, 119]
CK/IH-901/M1	Antiproliferation	G1 phase arrest [120]. Inhibits telomerase activity and downregulates the human TERT gene [121]; induces mitochondria-dependent apoptotic pathway [122]; inhibits FGFR3 expression and signaling [52]; induces autophagy [123]
	Active tumor suppressors	Inhibits DNA methyltransferase 1 and reactivates epigenetically silenced genes. IC50: 20 ± 1.0 μg/mL [124]; upregulates cytochrome C, p53, and Bax expression [125]
	Inhibit cellular metabolism	CAMK-IV/AMPK pathways [126]; inhibits histone deacetylase activity [127]; modulates AMPK-COX-2 signaling [40]
	Anti-inflammation	Inhibits colonic inflammation and tumorigenesis promoted by Western diet. Inhibits tumor xenograft growth. Reduces EGFR and ErbB2 activation and Cox-2 expression [128]
	Inhibit tumor growth	Bid-mediated mitochondrial pathway [42]; increases Ca^2+ influx, mainly through TRPC channels and by targeting AMPK [129]
	Antimetastasis	Inhibits adhesion, invasion, and spontaneous metastatic growth. Inhibition of AP-1 and MAPK pathways [130]; suppresses the activation of the NF-κB pathway and inhibition of MMP-2/MMP-9 expression [131]
	Antiangiogenesis	Regulates MMP expression, as well as the activity of sphingosine kinase-1 and its related sphingolipid metabolites [132]; blockades of type IV collagenase secretion [133]
	Synergy and attenuation	Synergies with cisplatin, CTX [134]; increases radiosensitivity [135]; decreases the toxicity of irinotecan [136]
	Prevent tumorigenesis	Prevents tumorigenesis of aberrant crypts in C57BL:6 mice colonized with ginseng-hydrolyzing bacteria
Ginsenoside Rb1	Antiproliferation	Increases the expression levels of caspase-3 and caspase-8 [137]
	Antiangiogenesis	Inhibits the HGF/SF-induced chemoinvasion. Inhibits tyrosine kinase [10]; regulates pigment epithelium-derived factor through the estrogen β receptor [138]
	Attenuation	Reduces CTX-induced DNA damage and apoptosis effects [139]
	Chemoprevention	Induces cytochrome P450 1A1 expression. Aryl hydrocarbon receptor [140]
Ginsenoside Rb2	Antiproliferation	Increases the expression levels of caspase-3 and caspase-8 [137]
	Antimetastasis	Inhibits the adhesion and invasion and suppression of MMP-2 [141]
	Prevent tumorigenesis	Prevents the downregulation of gap junctional intercellular communication by TPA and hydrogen peroxide [142]
Ginsenoside Rb3	Antiproliferation	Inhibits DNA transferring and duplication [143]; inhibits RNF-α-induced NF-κB activity and inhibits COX-2 and iNOS mRNA levels [144]
	Synergy and attenuation	Increases cisplatin’s antiproliferative activity in MCF-7 cells [145]
Ginsenoside Rc	Antiproliferation	Antiproliferation of HCT-116 and HT-29 cells [146]
	Synergy and attenuation	Reverses MDR, reduces the activity of the efflux pump, enhances T cell proliferation, and increases the NK cell activity [147]
Ginsenoside Rd	Antiproliferation	Inhibits the chymotrypsin-like activity of 26S proteasome [148]; induces apoptosis and reduces oxidative stress and associates with DNA replication and repair, protein synthesis and degradation, mutagenesis, and metastasis [149]
	Antimetastasis	Blocks MMP activation and MAPK signaling pathways [55]
	Synergy and attenuation	Reverses MDR, reduces the activity of the efflux pump, enhances T cell proliferation, and increases the NK cell activity [147]
Ginsenoside Rk1	Antiproliferation	Induces apoptosis, upregulation of Fas, FasL, and Bax, and downregulation of procaspase-8 and procaspase-3, mutant p53, and Bcl-2 [59]
Ginsenoside Rs3	Antiproliferation	G1/S phase arrest. Elevates protein levels of p53 and and downregulates the activities of the cyclin-dependent kinases [60]
Ginsenoside F2	Antiproliferation	Induces apoptosis accompanied by protective autophagy. Activates intrinsic apoptotic pathway and mitochondrial dysfunction [150]
	Inhibit tumor growth	IC50: 49.9 ± 4.2 μM. Accumulation of ROS and activating the ASK-1/JNK signaling pathway [19]
	Antimetastasis	IC50: 50 μg/mL. Activation of caspase-3 and caspase-8 and inhibition of MMP-9 [151]
Ginsenosides Mb, Mc, and Mx	Antiproliferation	Antiproliferation of HCT-116 and HT-29 cells [146], as well as HL-60, HGC-27, Colon205, and Du145 cells [152]