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Table 3 Summary on the pharmacological action of Huachansu extract (HCS) and Bufalin (BF) reported in recent 10 years

From: New therapeutic aspects of steroidal cardiac glycosides: the anticancer properties of Huachansu and its main active constituent Bufalin

Cancer type Study type Pharmacological action Pathways involved Refs. Year
Bladder In vitro Growth inhibition (50–300 nM, 24H); G2/M arrest; apoptosis induction (T24, EJ) [BF] Bax/Bcl-2 ratio Fas, DR4, DR5, TRAIL, PARP cleavage↑; pro-caspase-3, -8, -9, Bcl-xL, Bid, XIAP, cIAP-1, cIAP-2↓ Hong et al. [43] 2012
In vitro Growth inhibition (50–200 nM, 24H); G0/G1 arrest; mitochondrial/apoptosis (T24) [BF] ROS production, cytochrome c, Apaf-1, AIF, caspase-3, -7, -9, Bax↑; ΔΨm, cyclin D, CDK4, cyclin E, CDK2, phospho-Rb, phospho-AKT Bcl-2↓ Huang et al. [29] 2012
In vitro Migration and invasion inhibition (5–100 nM, 24H) (T24) [BF] TIMP-1, -2, phospho-ERK↑; claudin-2, -3, -4, MMP-2, -9, Active-MMP-2, -9↓ Hong et al. [151] 2013
In vitro Sensitization of TRAIL-mediated apoptosis (2.5–10 nM, 24H) (T24) [BF] Caspase-9, pro-caspase-9, DR5, degradation of poly (ADP-ribose) polymerase↑ Kang et al. [152] 2017
Bone In vivo Relieves cancer-induced pain and bone destruction (Walker 256 cells) [BF] OPG↑; RANKL, serum TRACP5b, ICTP, PINP↓ Ji et al. [83] 2017
Breast In vitro Sensitization of TRAIL-mediated apoptosis (0.02–0.25 μM, 24H) (MCF-7, MDA-MB-231) [BF] Mcl-1, Bcl-xL, p-STAT3↓ Dong et al. [153] 2011
In vitro Growth inhibition (50 nM, 24H); apoptosis induction; enhanced TRAIL-induced apoptosis (MCF-7, MDA-MB-231) [BF] DR4, DR5, p-ERK, p-JNK, p-p38, cleaved-PARP↑; pro-caspase-8, Cbl-b↓ Yan et al. [125] 2012
In vitro and in vivo Growth inhibition (1–5 nM, 24H); promote coactivators’ protein degradation (MCF-7) [BF] SRC-3 mRNA expression, SRC-3 protein degradation↑; intrinsic transcriptional activities of SRC-1 and SRC-3↓ Wang et al. [56] 2014
In vitro Sensitization of TRAIL-mediated apoptosis (50 nmol/L, 24H); redistributing death receptors in lipid rafts (MCF-7, MDA-MB-231) [BF] DR4, DR5, cleaved-PARP, cleaved-caspase-8↑; caspase-8↓ Yan et al. [154] 2014
In vitro and in vivo Growth inhibition (100 ng/mL, 8H); mitochondrial/apoptosis (MCF-7) [BF, BF-BCS-NPs] Intracellular ROS, BAX, cleaved-caspase-3↑; ΔΨm, Bcl-2, survivin↓ Tian et al. [104] 2014
In vitro Growth inhibition; apoptosis (10–50 nmol/L, 48H) (MCF-7/ADR, MDA-MB-231)[BF] PARP cleavage, miR-155-5p expression↑; DNMT1, DNMT3a, FOXO3a↓ Wang et al. [126] 2016
In vitro and in vivo Growth inhibition (12–200 nM) (LM3-3) [BF, phospho-BFs] Synergizes with Gefitinib; SRC-3↓ Song et al. [55] 2015
In vitro Growth inhibition (4–8 nM, 48H) (MDA-MB-231); enhanced HDAC inhibitors induced apoptosis [BF] ↑;SRC-3p-Akt, Bcl-2↓ Zou et al. [155] 2016
In vitro and in vivo Promote inflammatory response (0.001–1 μM, 12H) (MDA-MB-231) [BF] p65 translocation; PKC-induced COX-2 and IL-8, PGE2, p-JNK, p-p38, p-ERK, TPA-induced MMP-3 protein and mRNA expression↑ Chen et al. [38] 2017
Cervical In vitro and in vivo Growth inhibition (0.05–0.2 μM, 24H); G2/M arrest; apoptosis; migration and invasion inhibition (0.01–0.04 μM, 24H) (Siha, Hela) [BF] BAX, P21, p27, E-cadherin, GSK3β↑;Bcl-2, Bcl-xL, cyclin A, cyclin B1, CDK2, MMP-9, SNAIL1, integrin α2, integrin β5, FAK, p-FAK(Tyr397), p-GSK3β(Ser389), AKT1, p-AKT(Ser473)↓ Liu et al. [80] 2016
In vitro Growth inhibition (0–50 nM, 24H); apoptosis induction (Hela) [BF] HSP27, vimentin, HNRPK↓ Pan et al. [127] 2012
Colorectal In vitro Growth inhibition (25–100 nM, 48H); G2/M arrest; autophagy induction (HT-29, Caco-2) [BF] LC3-II, ROS, Atg-5, Beclin-1, p-JNK2↑ Xie et al. [59] 2011
In vitro Growth inhibition (20, 80 nmol/L, 24H); G2/M arrest; apoptosis (SW620) [BF] PARP cleavage, cleaved-caspase-3, BAX/BCL-2 ratio↑;p-Stat3, p-ERK, livin↓ Zhu et al. [128] 2012
In vitro Growth inhibition (100 nM, 9H); mitotic arrest; G2/M arrest (HT-29, HCT-116) [BF] p-H3↑;HIF-1α, NF-κB, Plk1 expression↓ Xie et al. [156] 2013
In vitro and in vivo Anti-migration and anti-metastasis (3.12–50 nM, 12H) (HCT116), ex vivo micro vessel sprouting (HUVECs) [BF] miR-497 expression↑; VEGFA expression↓ Qiu et al. [130] 2014
In vitro and in vivo Growth inhibition (0.03–3 μΜ, 24–48H); G2/M arrest; apoptosis (HT116) [BF] PTEN, Bad, caspase-3 phosphorylation, caspase-3 cleavage↑; p-PTEN, p-AKT↓ Wang et al. [131] 2015
In vitro Anti-proliferation and anti-migration (10–50 nM, 48H); induce apoptosis; G2/M arrest (LoVo, SW620) [BF] Cyclin B1, p–cdc2, p21, cleaved-PARP, Bax, cleaved-caspase-7, -9, E-cadherin↑; Bcl-2, N-cadherin, β-catenin, CPSF4, hTERT↓; inhibit hTERT by down-regulating CPSF4 Zhang et al. [129] 2016
In vitro and in vivo Suppress growth of cisplatin-resistant cell rather than sensitive-one; reverse ABCB1-mediated multi-drug resistance (5–20 nM, 48H) (LoVo/ADR, HCT8/ADR, HCT8/ABCB1) [BF] ATPase activity of ABCB1↑; ABCB1↓ Yuan et al. [145] 2015
In vitro and in vivo Reverse cisplatin drug resistance (5 nM, 48H) (HCT116, LoVo HCT116-STSCscis, LoVo-STSCscis) [BF] CD133, CD44, OCT4, SOX2, NANOG, ABCG2 ↓ Sun et al. [146] 2017
Gallbladder In vitro Apoptosis induction (25–200 nmol/L, 48H); S-phase arrest; mitochondrial dysfunction induction (GBC-SD, SGC996) [BF] Cleaved-caspase-3, -9, cleaved-PARP ↑; Cyclin A, Cyclin B1, Cyclin D1, CDK1, NF-κB, Bcl-2, ΔΨm↓ Jiang et al. [45] 2014
Gastric In vitro Growth inhibition (100, 200 nmol/L, 24H); G2/M phase arrest; intrinsic apoptosis induction (SGC7901, MGC803) [BF] SPARC antagonizes bufalin-induced apoptosis; p-Src, p-Akt, p-ERK↑; ΔΨm, cyclin B1, cyclin A↓ Li et al. [134] 2015
In vitro Growth inhibition (25–200 nmol/L, 48H); apoptosis induction (SGC7901, MGC803)[BF] Bax, cleaved-PARP↑; Bcl-2, pro-caspase-3, miR-298 suppressed apoptosis↓ Zhao et al. [157] 2015
In vitro Proliferation inhibition (100 nM, 48H); cisplatin-sensitization; apoptosis induction (SGC7901, MKN-45, BGC823) [BF] p-AKT, p-GSK3β, p-mTOR, p-4EBP1, p-S6 K↓ Zhao et al. [158] 2016
In vitro G0/G1 phase arrest (50, 80 nmol/L, 48Η); caspase and mitochondrial-mediated apoptosis induction; ER stress induction; protective autophagy activation (SGC7901, BGC823) [BF] Cleaved-caspase-3, cleaved-PARP, Bax/Bcl-2, CHOP, p-eIF2a, p-JNK, LC3-II, Atg5, Beclin-1↑; LC3-I, p62↓
 Zhao et al. [159] 2017
Glioma In vitro Growth inhibition (20–80 nM, 24H); mitochondria-mediated apoptosis induction; autophagy activation (U87MG, LN229) [BF] ROS production, Bax, cytosolic cytochrome c, cleaved-PARP, cleaved-caspase-3, -4, LC3-II, p-AMPK, p-ACC, ATF6f, p-PERK, p-IRE1α, p-eIF2α, GRP78, GRP994, CHOP↑; Bcl-2, p-mTOR, p-4EBP1, p-p70S6K, PERK↓ Shen et al. [160] 2014
In vitro Proliferation inhibition (5–40 μM, 24H); cancer stem cell-like phenotypes inhibition; apoptosis induction (U251, U87) [BF] miR-203↑;OCT4, SOX2, SPARC↓ Liu et al. [161] 2017
HCC In vitro Growth inhibition (0.1–1 μΜ, 2H) (HepG2, PLC/PRF/5, SMMC7721) [BF] p-ERK, p-Akt, ATP1A3↑; FoxO3a↓ Li et al. [27] 2011
In vitro Growth inhibition (0.001–0.1 μmol/L, 24–72H); induction of fas- and mitochondria-mediated apoptosis (HepG2) [BF] Bax, cytochrome c, cleaved-caspase-3, -9, PARP cleavage ↑; ΔΨm, Bcl-2, pro-caspase-3, -9, -10, Bid ↓ Qi et al. [162] 2011
In vitro Anti-proliferation (50–250 nM, 48Η); enhances the anti-cancer effects of Sorafenib (6.25lM) (PLC/PRF/5, HepG2) [BF] Enhanced apoptotic cell death in combination with Sorafenib; p-Akt↑;p-ERK↓ Gao et al. [60] 2012
In vitro Growth inhibition (50–100 nM, 24H); G2/M arrest; autophagy induction (SK-HEP-1)[CS] Chk1, Wee1, LC3-II, Atg5, Atg7, Atg12, Beclin-1↑; Cyclin A, cyclin B, CDK1, p-CDK1(Thr161), Cdc25c, p-CDC25c(Ser198), p-Akt(Ser308), p-AKT(Ser473), p-mTOR(Ser2481), AKT kinase activity↓ Tsai et al. [135] 2012
In vitro Growth inhibition (10–100 nM, 48H); autophagy induction; apoptosis induction (HepG2) [BF] p-APMK, Beclin-1, LC3-II, p-p70S6K↑; p-mTOR, p62↓ Miao et al. [49] 2013
In vitro Growth inhibition; G2/M arrest (0.04 μM, 4–12H); autophagy induction (Huh7, Hep3B, HA22T) [BF] TNF, BECN-1, MAPK, ATG8↑; Bcl-2, Bid↓ Hsu et al. [30] 2013
In vitro Growth inhibition; anti-migration (10, 100 nmol/L, 48H); anti-invasion; anti-adhesion (HCCLM3, HepG2) [BF] GSK3β, E-cadherin↑; p-Akt, p-GSK3β, MMP-9, -2, β-catenin nuclear translocation↓ Qiu et al. [71] 2013
In vitro Growth inhibition (5, 10 nM, 48H); anti-migration and invasion (SK-Hep1) [BF] PI3K, p-Akt, NF-κB translocation, MMP-2, -9, FAK, Rho A, VEGF, MEKK3, MKK7, uPA↓ Chen et al. [68] 2013
In vitro Growth inhibition (50–100 nmol/L, 48H); apoptosis induction; ER stress induction; autophagy induction (Huh-7, HepG2) [BF] Beclin-1, p-JNK1, p-JNK2, IRE1, ATG5, LC3-I, LC3-II↑; p62↓ Hu et al. [163] 2014
In vitro Reverse multidrug resistance (1 nM, 48H); G0/G1 phase arrest (BEL-7402/5-FU) [BF] drug efflux pump activity, TS, MRP1, Bcl-xL/Bax ratio ↓ Gu et al. [164] 2014
In vivo Orthotopic growth inhibition, anti-metastasis (1 mg/kg and 1.5 mg/kg) (HCCLM3-R) [BF] p-Akt, GSK3β, E-cadherin↑; p-GSK3β, β-catenin, MMP-9, -2↓ Zhang et al. [72] 2014
In vitro Reverse Sorafenib resistance (50–200 nM, 48H); synergies with sorafenib to induce apoptosis (HepG2, HepG2-Sora, Huh7, Huh7-Sora) [BF] IRE1, CHOP, P-eIF2α↑; p-Akt↓ Zhai et al. [165] 2015
In vitro Anti-invasion and metastasis (0.085 μg/mL, 72H) (BEL-7402) [BF] E-cadherin, ALB↑; β-catenin, p-GSK-3β Ser9, MMP-7, COX-2, Cyclin D1, AFP↓ Gai et al. [66] 2015
In vitro and in vivo Synergies anti-angiogenic effect of sorafenib (2.5–10 nM, 48H); anti-migration; S-phase arrest (HUVECs, SMMC7721) [BF] p-ERK↑; VEGF, p-Akt, p-mTOR↓ Wang et al. [64] 2016
In vitro and in vivo Inhibits TGF-β1 induced EMT and invasion (10 nM, 24–72H) (SMMC7721) [BF] E-cadherin↑; N-cadherin, Vimentin, Snail, HIF-1α↓ Wang et al. [76] 2016
In vitro Growth inhibition (40–200 nmol/L, 24–48H); apoptosis induction (Hep3B)[BF] Apolipoprotein E (APOE) knockdown induced Na+/K+-ATPase, caveolin, PI3K/AKT/GSK3b and apoptosis signal cascades↑;Cyclin D1, Cdc25c, Cdc2↓ Liu et al. [166] 2016
In vitro Growth inhibition (0.04 μg/mL, 72H); S- and G2-phase arrest; apoptosis induction; anti-migration and invasion; adhesion inhibition (HCC-LM3) [BF] E-cadherin↑; β-catenin, MMP-2, -9, VEGF↓ Sheng et al. [67] 2016
In vitro Growth inhibition (0.1 mg/mL, 24H); apoptosis induction (HepG2, HLE) [HCS] Bcl-2↑;ΔΨm, Bax, Bid, cytochrome c Xia et al. [167] 2017
Leukemia In vitro Vitamin D-induced cell differentiation enhancing (7.5, 10, 12.5 nM, 24H); VDR transactivation activity enhancing (HL-60, THP-1, U937) [BF] 1,25(OH)2D3-induced CYP24A1, CD14, CAMP, PTGS1, CD11b, CDKN1A expression, nuclear VDR expression, histone acetylation and VDR recruitment to the CYP24A1 promoter, Erk MAP kinase activation↑ Amano et al. [168] 2009
In vitro Proliferation inhibition (5–80 nmol/L, 12–72H); apoptosis induction (NB4) [BF] Synergized with PD98059; caspase-3 activation↑; survivin expression↓ Zhu et al. [169] 2012
In vitro Reverse multidrug resistance (0.001–0.1 μM, 48H); S-phase arrest (K562, K562/VCR) [BF] Bax↑; MRP1, Bcl-xL↓ Zhai et al. [136] 2014
In vitro Growth inhibition (0.01–0.5 μmol/L, 48H); apoptosis induction; cell cycle arrest (HEL) [BF] WT1 gene methylation, DNMT3a, DNMT3b protein↑; WT1 mRNA expression↓ Wang et al. [137] 2017
Lung In vitro Growth inhibition (0.1 μM, 24–48H); apoptosis induction; ROS-dependent mitochondrial dysfunction (ASTC-a-1) [BF] ROS production, Bax translocation from cytosol to mitochondria, caspase-3 activation↑ Sun et al. [50] 2011
In vitro Growth inhibition (2.5–10 μM, 48–72H); apoptosis induction; G1-phase arrest (A549) [BF] Cyto C (Cytosol)/Cyto C (mitochondrial), cleaved-caspase-3, cleaved-PARP, p53, p21Waf↑; Bcl-2/Bax ratio, Cyclin D1, COX-2, p-VEGFR2, p-VEGFR1, p-EGFR, p-Akt, p-p38MAPK, p-NKκB, p-ERK1/2↓ Jiang et al. [46] 2010
In vitro Growth inhibition (20–100 nM, 48–72H); apoptosis induction (A549) [BF] Bax, cleaved-caspase-3↑; Bcl-2, livin, p-Akt↓ Zhu et al. [138] 2012
In vitro Growth inhibition (20 nM, 72H); reverses HGF-resistance to EGFR-TKIs; apoptosis induction (HCC827, PC-9, H1975) [BF] Cleaved-caspase-3, -9, cleaved-PARP↑; blockage of Met/PI3k/Akt pathway Kang et al. [170] 2013
In vitro Growth inhibition (1–4 μM, 24H); induce DNA condensation (NCI-H460) [BF] DNA-PK, BRCA1, 14-3-3-σ, MDC1, MGMT, P53↓ Wu et al. [70] 2014
In vitro Growth inhibition (2–8 ng/mL, 48H); apoptosis induction (A549) [BF] Cleaved-caspase-3, cytosol cytochrome c↑; ΔΨm↓ Ding et al. [41] 2014
In vitro TGF-β induced epithelial-to-mesenchymal transition and migration inhibition (50 nM, 24H) (A549) [BF] TGF-β receptor, I and II TGF-β induced E-cadherin, p-Smad2, p-Smad3↓ Zhao et al. [79] 2015
In vitro Invasion and migration inhibition (25–100 nM, 24–48H); cell adhesion inhibition (NCI-H460) [BF] RhoA, MMP-2, -9 expression, TIMP1 expression↑; MMP-2, -9 activity, NF-κB, PKC, GRB2, p-AKT, p-ERK, p-P38, p-JNK1/2, ROCK1, FAK, TIMP2↓ Wu et al. [70] 2015
In vitro Growth inhibition (5–20 nmol/L, 72H); cellular proteasome activity inhibition; ubiquitinated proteins accumulation (A549) [BF211] PSMB6 β1↓ Sun et al. [92] 2016
In vitro Growth inhibition (1–2 nM, 48H); enhanced HDAC inhibitors induced apoptosis (A549) [BF] SRC-3p-Akt, Bcl-2↓ Zou et al. [155] 2016
In vitro and in vivo Growth inhibition (1–4 μM, 12–48H); cell morphological changes induction; DNA condensation; apoptosis induction (H460) [BF] Cytochrome C, Apaf-1, active caspase-3, FasL/CD95, FasL, AIF, Endo G, caspase-9 activity, GADD153 mRNA expression, ROS production↑; pro-caspase-3, Bcl-2, GRP78 mRNA expression, ΔΨm↓ Wu et al. [150] 2017
In vitro and in vivo Growth inhibition (12.5–50 nM, 1–12H); apoptosis induction (A549) [BF] Cleaved-caspase-3, cleaved-PARP, Caspase-3 activity↑; p-Src↓ Liu et al. [36] 2016
In vitro Inhibits gefitinib resistant cell migration and invasion (2.5–10 nM, 24–48H) (NCI-H460) [BF] p-p38, p65↑; SOS-1, MMP-2, RhoA, N-Cadherin, E-Cadherin↓ Huang et al. [74] 2016
In vitro Growth inhibition (25–100 nM, 6–48H); apoptosis induction (H1975) [BF] Mcl-1 protein degradation, cleaved-PARP, cleaved-caspase-3, Bax, Bak↑; p-GSK-3β, Bcl-1, Bcl-2, Bcl-xL↓ Kang et al. [171] 2017
In vitro Growth inhibition (1–100nmoL/L, 24–72H); apoptosis induction; S-phase arrest (A549) [BF] Caspase-3↑ Zhang et al. [172] 2017
Melanoma In vitro Growth inhibition (150–550 nM, 24–48H); apoptosis induction (A375.S2) [BF] ROS production, intracellular Ca2+ production, NO formation; cleaved-caspase-3, -8, -9, cytochrome c, AIF, Endo G, Bax, Fas, FasL, GRP78; ΔΨm, Bcl-xL↓ Hsiao et al. [44] 2012
Myeloma In vitro Growth inhibition (20 nM, 48H); apoptosis induction; G2/M arrest (U929, U266) [BF] Chemosensitivity↑; PARP1↓ Huang et al. [173] 2013
In vitro and in vivo Growth inhibition (12 nM, 12–48H); synergistic with MK2206 surpassed bortezomib resistance (U929, U266) [BF] p-Akt, p-mTOR↑; p-P70, IL-6 secretion↓ Xiang et al. [147] 2017
Oral In vitro Growth inhibition (125 nM, 24H); G0/G1 phase arrest; apoptosis induction (CAL27)[BF] Cytochrome c, Apaf-1, AIF, cleaved-caspase-3, -9↑; p-Akt, Cyclin D1, p-Bad↓ Tsai et al. [139] 2012
In vitro Growth inhibition (50–150 nM, 24–48H); apoptosis induction (CAL27) [BF] Intracellular ROS accumulation, p-JNK, p-p38, p-c-Jun↑; hTERT expression ↓ Tian et al. [140] 2015
Osteosarcoma In vitro Growth inhibition (25–50 nM, 24–48H); anti-invasion and migration (U2OS) [BF] SOS-1, JNK1/2, ERK1/2, p-38, MMP-7, -9 enzyme activity↓ Chueh et al. [69] 2011
In vitro and in vivo Growth inhibition (25 nM, 24H); apoptosis induction; G2/M arrest (U2OS, U2OS/MTX300) [BF] Cleaved-PARP↑; Hsp27, p-Akt, P65↓ Xie et al. [86] 2012
In vitro Inhibition of differentiation and proliferation (10 μM, 72Η) (hMG63-derived cancer stem cell) [BF] CD133↓ Chang et al. [174] 2014
In vitro Growth inhibition (10–40 nM, 24H) (MG-63) [BF] ROS production, mitochondrial membrane hyperpolarization, Apaf-1, cleaved-PARP, cleaved-caspase-3, -7, -9↑; Bcl-2/Bax ratio↓ Wang et al. [51] 2014
In vitro Inhibition of differentiation and proliferation (10 μΜ, 8 days) (Primary osteosarcoma stem cell C1OS) [BF] Cleaved-caspase-3, miR-148a↑; ALDH1, hTERT, Nanog. CD133, Notch, Bmi-1↓ Chang et al. [175] 2015
In vitro Growth inhibition (10–50 μg/L, 6–24H); apoptosis induction (U-2OS) [BF] Cytosol/mitochondrial cytochrome c, cleaved-PARP, cleaved-caspase-3, -9, Bax↑; ΔΨm, PARP, Bcl-2↓ Chen et al. [40] 2016
In vitro Growth inhibition (0.05–10 μM, 24H); apoptosis induction (U-2OS, Saos-2) [BF] ROS production, BBC3↑; miR221↓ Zhang et al. [141] 2016
In vitro Growth inhibition (200 nM, 6–48H); apoptosis induction (U-2OS) [BF] Ca2+ release, caspase-3, -8, -9 activity, cytochrome c, Fas-L, cleaved-PARP, Calpain 1, ATF-6α, GRP-78, caspase-4↑; ΔΨm, Bcl-2, Bcl-xL↓ Lee et al. [176] 2017
Ovarian In vitro Growth inhibition (1 ng/mL, 48H); G0/G1 arrest; apoptosis induction [BF] (SK-OV-3, OMC-3) p21, cleaved-caspase-9↑; Cyclin A, Cyclin D3, Bcl-2, Bcl-xL↓ Takai et al. [132] 2008
In vitro Growth inhibition (1–100 ng/mL, 48H); apoptosis induction (SKOV3, ES-2) [BF] miR-183 downregulation enhanced bufalin-induced growth inhibition and apoptosis Chen et al. [177] 2016
Pancreatic In vitro and in vivo Growth inhibition (0.001–0.1 μM, 48H); apoptosis induction; enhance sensitivity to gemcitabine (Bx-PC3, MiaPaCa2, Panc-1) [BF] ASK1, p-JNK, cleaved-caspase-3↑; Ki-67, Bcl-2↓ Chen et al. [148] 2012
In vitro Growth inhibition (50–200 nM,48H); G2/M arrest; apoptosis induction; enhanced gemcitabine chemosensitivity (Panc-1, CFPAC-1) [BF] Bax, P21↑; Bcl-2, pro-caspase-3, -9, CyclinB1, CDK1↓ Li et al. [47] 2014
In vitro Growth inhibition (50–150 nM, 24–48H); mitochondria-dependent apoptosis induction; (Capan-2)[BF] p-JNK, p-p38, p-c-Jun, intracellular ROS accumulation↑; hTERT expression↓ Tian et al. [140] 2015
In vitro and in vivo Cancer stem cells formation inhibition (50 nM, 24H) (MiaPaCa2/GEM) [BF] CD24 expression, ESA expression, PTCH1, PTCH2, Gli1↓ Wang et al. [82] 2016
In vitro and in vivo Growth inhibition (0.1–10 μM, 24H); S-phase arrest (SW1990, BxPc3) [BF] c-Myc, NF-κB↓ Liu et al. [149] 2016
Prostate In vitro Growth inhibition (0.1–10 μM, 24H); apoptosis induction (LNCaP, PC3, DU145) [BF] Caspase-3 activity, caspase-9 activity, intracellular Ca2+ Yeh et al. [178] 2003
In vitro Growth inhibition (15 μM, 24H); apoptosis induction (PC3) [BF] miR-181a induction enhanced bufalin-induced growth inhibition and apoptosis; miR-181a expression, caspase-3 activity↑; Bcl-2↓ Zhai et al. [179]. 2013
Renal In vitro Induce new high density glycogen-microtubule structures formation (1–20 nM, 0–4.5H) (ACHN) [BF] KATPase-induced ERK1/2 phosphorylation↑ Fridman E et al. [180] 2012
Tongue In vitro Growth inhibition (100–500 nM, 48H); G2/M arrest; mitochondria-dependent apoptosis (SCC-4) [BF] Ca2+, NO production, DR5 expression, caspase-9 expression↑; Bcl-2, Bid, calpain 1, ATF-6β, ΔΨm, ROS production↓ Chou et al. [143] 2017