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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]

K−ATPase-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