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Cancer is characterised by uncontrolled cell division and abnormal cell growth, which is largely caused by a variety of gene mutations. There are continuous efforts being made to develop effective cancer treatments as resistance to current anticancer drugs has been on the rise. Natural products represent a promising source in the search for anticancer treatments as they possess unique chemical structures and combinations of compounds that may be effective against cancer with a minimal toxicity profile or few side effects compared to standard anticancer therapy. Extensive research on natural products has shown that bioactive natural compounds target multiple cellular processes and pathways involved in cancer progression.
Cell Lines | Mechanism of Action | Concentration Used | Efficacy/IC50 (Exposure Time) | References | |
---|---|---|---|---|---|
Colorectal cancer | RKO | Inhibit cell proliferation Induce G1 phase cell cycle arrest Induce apoptosis ↓ Bcl-xL; ↑ Caspase-3 & caspase-9 |
0–150 μM | 46.76 μM (68 h) |
[25] |
HCT116, HCT116-CH2, HCT116-CH3 | Inhibit cell proliferation Induce G0/G1 & G2/M phase cell cycle arrest: ↓ cyclin D1 & A1; ↑ p53 phosphorylation Induce apoptosis: ↓ Caspase-3; ↓ Bcl-2; ↑ Bax protein |
25 μM Honokiol with 2.5 or 5.0 Gy IR |
N/A | [26] | |
HT-29 | Inhibit cell growth & proliferation Induce G1 phase cell cycle arrest: ↓ Cdk1 & cyclin B1 |
0–50 μM followed by 0–5 Gy IR |
23.05 μM (24 h) 13.24 μM (72 h) |
[27] | |
HCT116 & SW480 | Inhibit cell proliferation via Inhibition of Notch signalling: ↓ Notch1 & Jagged-1; ↓ Hey-1 & Hes1; ↓ γ-secretase complex; ↓ Skip1 Induce apoptosis: ↑ caspase-3/-7 activity; ↓ Bcl-2 & Bcl-xL; ↑ Bax protein; ↓ cyclin D1 & c-Myc; ↑ p21WAF1 protein Inhibit primary and secondary colonosphere formation |
0–50 μM | N/A | [28] | |
RKO & HCT116 | Inhibit cell viability Induce apoptosis: ↑ caspase-3, caspase-8 & caspase-9 activation; ↑ DR5 & cleaved PARP proteins; ↑ survivin protein; ↑ phosphorylated p53 & p53 proteins; ↓ PUMA protein |
0–60 μM | RKO: 38.25 μM (24 h) HCT116: 39.64 μM (24 h) |
[29] | |
Blood cancer | B-CLL | Inhibit cell viability Induce apoptosis: ↑ caspase-3 activity; ↑ caspase-8 & caspase-9 activation; ↓ caspase-9; ↑ Bax protein; ↓ Mcl-1 protein |
0–100 μM | 49 μM (6 h) 38 μM (24 h) |
[30] |
Raji, Molt-4 | Inhibit cell growth: ↓ p65; ↓ NF-κB Induce apoptosis: ↑ JNK activation Increase ROS activity: ↑ Nrf2 & c-Jun protein activation |
0–2.5 μM | Raji: 3.500 μM (24 h) 0.092 μM (72 h) Molt-4: 0.521 μM (24 h) |
[31] | |
Breast cancer | MCF-7, MDA-MB-231, SKBR-3, ZR-75-1, BT-474 | Inhibit cell viability and growth: ↓ EFGR; ↓ MAPK/PI3K pathway activity Induce apoptosis: ↑ PARP protein degradation; ↓ caspase-8; ↑ Bax proteins Induce G1 phase cell cycle arrest: ↓ cyclin D1; ↑ p21 & p27 |
0–100 μM | MCF-7: 40 μM (24 h) MDA-MB-231: 33 μM (24 h) SKBR-3: 29 μM (24 h) ZR-75-1: 39 μM (24 h) BT-474: 50 μM (24 h) |
[32] |
MCF-7, MDA-MB-231 | Inhibit cell clonogenicity Inhibit cell anchorage-dependent colony formation Inhibit cell growth, migration & invasion: ↓ pS6K & 4EBP1 phosphorylation; ↑ AMPK activation; ↓ mTORC1 function; ↑ LKB1 & cytosolic localisation |
1–25 μM | N/A | [33] | |
MCF-7, MDA-MB-231, SUM149, SUM159 | Inhibit cell migration & invasion: ↑ AMPK phosphorylation; ↑ LKB1 Inhibit stem-like characteristics: ↓ Oct4, Nanog & Sox4 protein; ↓ STAT3; ↓ iPSC inducer mRNA |
5 μM | N/A | [34] | |
MCF-7, MDA-MB-231, T47D, SKBR-3, Zr-75, BT-474 | Inhibit cell growth: ↓ PI3K/Akt/mTOR signalling Inhibit cell invasion Induce G0/G1 phase cell cycle arrest: ↓ cyclin D1 & cyclin E; ↓ Cdk2 & c-myc; ↑ PTEN Induce apoptosis: ↑ caspase-3, caspase-6 & caspase-9 activation |
0–40 μM | MCF7: 34.9 μM (24 h) 13.7 μM (48 h) 13.5 μM (72 h) 10.5 μM (96 h) MDA-MB-231: 56.9 μM (24 h) 44.4 μM (48 h) 16.0 μM (72 h) 12.0 μM (96 h) T47D: 47.7 μM (24 h) 41.6 μM (48 h) 17.6 μM (72 h) 7.1 μM (96 h) SKBR-3: 76.1 μM (24 h) 68.1 μM (48 h) 62.7 μM (72 h) 15.7 μM (96 h) ZR-75: 71.1 μM (24 h) 58.1 μM (48 h) 28.7 μM (72 h) 14.5 μM (96 h) BT-474: 80.2 μM (24 h) 65.6 μM (48 h) 39.5 μM (72 h) 15.1 μM (96 h) |
[35] | |
MDA-MB-231 | Inhibit cell proliferation: ↓ c-Src/EGFR-mediated signalling pathway; ↓ c-Myc protein Induce G0/G1 phase cell cycle arrest: ↓ cyclin A, cyclin D1 & cyclin E; ↓ Cdk2, Cdk4 & p-pRbSer780; ↑ p27Kip−1 Induce apoptosis: ↑ caspase-3, caspase-8 & caspase-9 cascade; ↓ Bcl-2 & Bid protein; ↑ PARP cleavage |
0–100 μM | 59.5 μM (72 h) | [36] | |
Lung cancer | A549 | Inhibit cell growth & proliferation Induce G0/G1 phase cell cycle arrest: ↓ Cdk1 & cyclin B1 |
0–50 μM | 12.51 μM (24 h) 7.75 μM (72 h) |
[27] |
A549, H460, H226, H1299 | Reduce invasive potential Inhibit PGE2-induced cell migration: ↓ PGE2 production ↓ COX-2 ↑ β-catenin degradation ↓ NF-κB/p65 activity ↓ IKKα |
0–20 μM | N/A | [37] | |
A549, H1299 | Inhibit cell viability and growth: ↓ class I HDAC proteins; ↓ HDAC activity; ↑ histone acetyltransferase (HAT) activity; ↑ histone H3 & H4 Induce G1 phase cell cycle arrest: ↓ cyclin D1 & cyclin D2; ↓ Cdk2, Cdk4 & Cdk6 |
0–60 μM | N/A | [38] | |
H460 & A549 | Inhibit cell proliferation Induce apoptosis: ↑ cathepsin D; ↑ cleaved PARP; ↑ caspase-3 Inhibit autophagy: ↑ p62; ↑ LC3-II |
0–60 μM | H460: ~30 μM (48 h) A549: ~40 μM (48 h) |
[39] | |
Pc9-BrM3 & H2030-BrM3 (brain metastatic) | Inhibit cell proliferation and cell invasion: ↓ STAT3 protein phosphorylation; ↓ STAT-3 mediated mitochondrial respiratory function | 0–50 μM | PC9-BrM3: 28.4 μM (48 h) H2030-BrM3: 25.7 μM (48 h) |
[40] | |
H23, A549 & HCC827 | Inhibit cell growth Induce G1 phase cell cycle arrest: ↓EGFR; ↓ class I HDAC; ↓ class IIb HDAC6 activity; ↑ Hsp90 acetylation & EGFR degradation |
0–40 μM | A549: 23.55 μM (24h) |
[41] | |
H460, A549, H358 | Inhibit cell growth: ↓ c-RAF, ERK & AKT phosphorylation Inhibit colony formation capacity Induce apoptosis: ↑ Bax protein; ↓ Bcl-2 protein; ↑ PARP cleavage Induce G1 phase cell cycle arrest: ↓ cyclin D1; ↑ p21 & p27; ↓ P70S6k kinase activity Induce autophagy: ↑ LC3-I conversion to LC3-II; ↑ Sirt3 mRNA & protein; ↓ Hif-1α protein |
0–80 μM | H460: 30.42 μM (72 h) A549: 50.58 μM (72 h) H358: 59.38 μM (72 h) |
[42] | |
A549 & 95-D | Inhibit cell viability Induce apoptosis: ↑ ER stress signalling pathway activation; ↑ GRP78, phosphorylation PERK & phosphorylated IRE1α; ↑ cleaved caspase-9 & CHOP; ↓ Bcl-2 protein; ↑ Bax, caspase-3 & caspase-9 Inhibit cell migration |
0–60 μM | N/A | [43] | |
CH27, H460 & H1299 | Inhibit cell growth Induce apoptosis: ↓ Bcl-XL; ↑ mitochondrial cytochrome c release; ↑ BAD protein; ↑ caspase-1, caspase-2, caspase-3, caspase-6, caspase-8 & caspase-9 activity; ↑ PARP cleavage |
0–100 μM | CH27: 40.9 μM (24 h) H460: 41.4 μM (24 h) H1299: 34.7 μM (24 h) |
[17] | |
MSTO-211H | Inhibit cell viability Induce apoptosis: ↑ PARP cleavage; ↑ caspase-3 activation; ↓ Bid & Bcl-xL protein; ↑ Bax protein; ↓ Mcl-1 & survivin protein; ↓ Sp1 Induce G1 phase cell cycle arrest: ↓ cyclin D1 |
0–22.5 μM | N/A | [44] | |
Skin cancer | SK-MEL2 & MeWo | Inhibit cell growth & cell proliferation Induce apoptosis via DNA degradation Induce cell death via mitochondrial depolarization |
0–100 μM | N/A | [45] |
A431 | Inhibit cell viability & proliferation Induce G0/G1 phase cell cycle arrest: ↓ cyclin A, cyclin D1, cyclin D2 & cyclin E; ↓ Cdk2, Cdk4 & Cdk6; ↑ p21 & p27 Induce cell apoptosis: ↑ PARP |
0–75 μM | N/A | [46] | |
B16-F10 | Inhibit cell proliferation Induce cell death: ↑ Autophagosome (vacuoles) formation; ↓ cyclin D1; ↓ AKT/mTOR & Notch signalling |
0–50 μM | N/A | [47] | |
B16/F-10 & SKMEL-28 | Inhibit cell proliferation & viability: ↓ Notch signalling; ↓ TACE & γ-secretase complex proteins Inhibit clonogenicity Induce G0/G1 phase cell cycle arrest Induce autophagy: ↑ autophagosome formation; ↑ LC3B cleavage Inhibit cell stemness: ↓ CD271, CD166, Jarid1B & ABCB5 |
0–60 μM | N/A | [48] | |
UACC903 | Inhibit cell growth & proliferation | 0–50 μM | 7.45 μM (24 h) 5.10 μM (72 h) |
[27] | |
SKMEL-2 | Inhibit cell proliferation & viability Induce apoptotic death: ↑ caspase-3, caspase-6, caspase-8 & caspase-9; ↑ PARP cleavage; ↓ procaspase-3, procaspase-8 & procaspase-9 Induce G2/M phase cell cycle arrest: ↓ cyclin B1, cyclin D1, cyclin D2 & PCNA; ↓ Cdk2 & Cdk4; ↑ p21 & p53 |
0–100 μM | N/A | [49] | |
UACC-62 | Inhibit cell proliferation & viability Induce apoptotic death: ↑ caspase-3, caspase-6, caspase-8 & caspase-9; ↑ cleaved PARP; ↓ procaspase-3, procaspase-8 & procaspase-9 Induce G0/G1 phase cell cycle arrest: ↓ cyclin B1, cyclin D1 & cyclin D2; ↓ Cdk2, Cdk4 & Cdc2p34; ↓ p21 & p27 |
0–100 μM | N/A | [49] | |
Renal cancer | A498 | Inhibit cell proliferation Inhibit colony formation capability Inhibit cell migration and invasion: ↓ Epithelial-mesenchymal transition (EMT); ↓ cancer stem cells (CSC) properties; ↑ miR-141; ↓ ZEB2 Inhibit tumoursphere formation |
0–80 μM | ~12 μM (72 h) | [50] |
Cervix cancer | KB-3-1, KB-8-5, KB-C1, KB-V1 | Inhibit cell viability: ↓ EGFR-STAT3 signalling Induce mitochondria-dependent & death receptor-dependent apoptosis: ↓ Bcl-2, Mcl-1 & survivin; ↑ PARP & caspase-3 cleavage; ↑ mitochondrial release of cytochrome c; ↑ DR5 Enhances in vitro cytotoxicity of Paclitaxel |
0–75 μM | KB-3-1: 12.56 μM (72 h) KB-8-5: 12.08 μM (72 h) KB-C1: 11.40 μM (72 h) KB-V1: 10.39 μM (72 h) |
[23] |
Pancreatic cancer | MiaPaCa & Colo-357 | Suppress plating efficiency of cells Reduce anchorage-independent clonogenicity growth Suppress migration and invasion ability |
0–5 μM | N/A | [51] |
MiaPaCa & Panc1 | Inhibit cell growth Induce G1 phase cell cycle arrest: ↓ cyclin D1 & cyclin E; ↓ Cdk2 & Cdk4; ↑ p21 & p27 Induce apoptosis: ↓ Bcl-2 & Bcl-xL proteins; ↑ Bax protein; ↓ IKB-α phosphorylation; ↓ NF-κB constitutive activation |
0–60 μM | MiaPaCa: 43.25 μM (24 h) 31.08 μM (48 h) 18.54 μM (72 h) Panc1: 47.44 μM (24 h) 34.17 μM (48 h) 21.86 μM (72 h) |
[52] | |
Thyroid cancer | ARO, WRO | Inhibit cell growth & proliferation: ↓ ERK, JNK & p37 activation and expression; ↓ mTOR & p70S6K Inhibit colony formation Induce apoptosis: ↑ PARP cleavage; ↑ caspase-3, caspase-8 & PARP activation; ↓ PI3K/AKT & MAPK pathways Induce G0/G1 cell cycle arrest: ↓ cyclin D1; ↓ Cdk2 & Cdk4; ↑ p21 & p27 Induce autophagy & autophagy flux: ↑ LC3-II |
ARO & WRO: 0–60 μM SW579: 0–40 μM |
ARO: 36.3 μM (24 h) 40.1 μM (48 h) 44.8 μM (72 h) WRO: 37.7 μM (24 h) 31.8 μM (48 h) 30.7 μM (72 h) SW579: 19.9 μM (24 h) 10.5 μM (48 h) 8.8 μM (72 h) |
[53] |
Nasopharyngeal cancer | HNE-1 | Inhibit cell growth Induce apoptosis Induce G1 phase cell cycle arrest |
0–150 μM (Honokiol & ATNH—Active targeting nanoparticles-loaded honokiol) | Honokiol: 144.71 μM (24 h) ATNH: 69.04 μM (24 h) |
[22] |
Brain cancer | U251 | Inhibit cell growth Inhibit cell proliferation Induce apoptosis |
0–120 μM | 61.43 μM (24 h) | [54] |
T98G | Inhibit cell viability Inhibit cell invasion Induce cell apoptosis: ↑ Bax protein; ↓ Bcl-2; ↑ Bax/Bcl-2 ratio |
0–50 μM | N/A | [55] | |
GBM8401 (Parental) & GBM8401 SP |
Inhibit cell proliferation & viability Induce sub-G1 phase cell cycle arrest Induce apoptosis: ↓ Notch3/Hes1 pathway |
0–20 μM | GBM8401 (Parental): 5.30 μM (48 h) GBM8401 SP: 11.20 μM (48 h) |
[29] | |
U251 & U-87 MG | Inhibit cell viability & proliferation: ↓ PI3K/Akt & MAPK/Erk signalling pathways Inhibit cell invasion & migration: ↓ MMP2 & MMP9; ↓ NF-κB-mediated E-cadherin pathway Inhibit colony formation Induce apoptosis: ↓ Bcl-2, p-AKT & p-ERK; ↑ Bax protein; ↑ caspase-3 cleavage; ↓ EGFR-STAT3 signalling Reduce spheroid formation: ↓ CD133 & Nestin protein |
0–60 μM | U251: 54.00 μM (24 h) U-87 MG: 62.50 μM (24 h) |
[56] | |
DBTRG-05MG | Inhibit cell growth Induce apoptosis: ↓ Rb protein; ↑ PARP & Bcl-x(S/L) cleavage Induce autophagy: ↑ Beclin-1 & LC3-II |
0–50 μM | ~30 μM | [57] | |
U87 MG (Human) BMEC (Mouse) |
Inhibit cell viability Inhibit epithelial-mesenchymal transition (EMT): ↓ Snail, β-catenin & N-cadherin; ↑ E-cadherin Inhibit cell adhesion & invasion: ↓ VCAM-1; ↓ phosphor-VE-cadherin-mediated BMEC permeability |
0–20 μM | U87MG: 22.66 μM (24 h) BMEC: 13.09 μM (24 h) |
[58] | |
U87 MG | Inhibit cell viability Induce G1 phase cell cycle arrest: ↑ p21 & p53; ↓ cyclin D1; ↓ Cdk4 & Cdk6; ↓ p-Rb protein; ↓ E2F1 Induce apoptosis: ↓ procaspase-3; ↑ caspase-8 & caspase-9 activity |
0–100 μM | 52.70 μM | [59] | |
Bone cancer | HOS & U20S | Inhibit cell proliferation Inhibit colony formation Induce G0/G1 phase cell cycle arrest: ↓ cyclin D1 & cyclin E; ↓ Cdk4 Induce mitochondria-mediated apoptosis: ↑ caspase-3 & caspase-9 activation; ↑ PARP cleavage; ↓ Bcl-2, Bcl-xL & survivin; ↑ ERK activation; ↓ proteasome activity; ↑ ER stress and subsequent ROS overgeneration; ↑ GRP78 Induce autophagy: ↑ Atg7 protein activation; ↑ Atg5; ↑ LC3B-II |
0–30 μM | HOS: 17.70 μM (24 h) U20S: 21.50 μM (24 h) |
[60] |
SAOS-2, HOS, 143B, MG-63 M8, HU09, HU09 M132 Dunn, LM5, LM8 & LM8-LacZ (Mouse) |
Inhibit cell metabolic activity Inhibit cell proliferation Inhibit cell migration Induce rapid cell death via Honokiol-provoked vacuolation |
0–150 μM | (72 h) SAOS-2: 48.38 μM HOS: 51.38 μM 143B: 41.63 μM MG-63M8: 34.88 μM HU09: 59.25 μM HU09M132: 31.88 μM (72 h) Dunn: 36.00 μM LM5: 30.00 μM LM8: 31.13 μM |
[61] | |
Saos-2 & MG-63 | Inhibit cell viability Induce apoptosis: ↑ caspase-3 & PARP cleavage; ↑ Bax protein; ↓ Bcl-2; ↓ PI3K/AKT signalling pathway; ↓ miR-21 |
0–100 μM | Saos-2: 37.85 μM (24 h) MG-63: 38.24 μM (24h) |
[62] | |
Oral cancer | OC2 & OCSL | Inhibit cell growth Induce G0/G1 phase cell cycle arrest: ↑ cyclin E accumulation; ↑ p21 & p27; ↓ cyclin D1, ↓ Cdk2 & Cdk4 Induce apoptosis: ↓ caspase-8 & caspase-9; ↑ caspase-3 cleavage; ↓ Bid protein Induce autophagy and autophagic flux: ↑ LC3-II; ↓ Akt/mTORC1 pathway; ↑ AMPK signalling pathway; ↑ p62 |
0–60 μM | OC2: 35.00 μM (24 h) 22.00 μM (48 h) OCSL: 33 μM (24 h) 13 μM (48 h) |
[18] |
HN-22 & HSC-4 | Inhibit cell viability Induce apoptosis: ↓ Sp1 protein; ↑ p21 & p27; ↑ PARP & caspase-3 activation; ↓ Mcl-1 & survivin protein Induce G1 phase cell cycle arrest: ↓ cyclin D1 |
0–37.5 μM | HN-22: 26.63 μM (48 h) HSC-4: 30.00 μM (48 h) |
[63] | |
Liver cancer | HepG2 | Inhibit cell growth & proliferation: ↓ β-catenin protein Induce apoptosis: ↑ BAD protein; ↓ Bcl-2 protein Upregulation of BAD protein expression Downregulation of Bcl-2 protein level |
0–2 μM | N/A | [64] |
SMMC-7721 | Inhibit cell growth Induce G0/G1 phase cell cycle arrest Induce apoptosis: ↓ mitochondrial potential; ↑ ROS production; ↓ Bcl-2 protein; ↑ Bax protein |
0–37.5 μM | N/A | [65] | |
HepG2, HUH7, PLC/PRF5, Hep3B | Inhibit cell proliferation: ↓ STAT3 activation; ↓ IL-induced Akt phosphorylation; ↓ c-Src activation; ↓ JAK1 & JAK2; ↑ SHP-1 protein Induce sub-G1 phase cell cycle arrest: ↓ cyclin D1 Downregulation of cyclin D1 level Induce apoptosis: ↓ Bcl-2 & Bcl-xL; ↓ survivin & Mcl-1 protein; ↑ caspase-3 activation; ↑ PARP cleavage Enhance apoptotic effect of doxorubicin & paclitaxel |
0–100 μM | N/A | [24] | |
Ovarian cancer | A2780s & A2780cp | Inhibit cell growth Induce apoptosis |
0–100 μM | A2780s: 36.00 μM (48 h) A2780cp: 34.70 μM (48 h) |
[66] |
SKOV3 & Caov-3 | Inhibit cell proliferation and growth Inhibit colony formation Induce apoptosis: ↑ AMPK pathway activation; ↑ caspase-3, caspase-7 & caspase-9 activation; ↑ PARP cleavage Induce G0/G1 phase cell cycle arrest Inhibit cell migration and invasion |
0–100 μM | SKOV: 48.71 μM (24 h) Caov-3: 46.42 μM (24 h) |
[20] | |
SKOV3, COC1, Angelen & A2780 | Inhibit cell proliferation Induce cell apoptosis: ↓ Bcl-xL; ↑ BAD protein; ↑ caspase-3 activation Induce G1 phase cell cycle arrest |
0–93.75 μM | SKOV3: 62.63 μM (24 h) COC1: 73.50 μM (24 h) Angelen: 61.50 μM (24 h) A2780: 55.85 μM (24 h) |
[67] | |
Prostate cancer | PC-3 & LNCaP | Inhibit cell viability Induce G0/G1 phase cell cycle arrest: ↓ cyclin D1 & cyclin E; ↓ Cdk2, Cdk4 & Cdk6; ↑ p21 & p53; ↓ Rb & E2F1 proteins; ↓ Rb phosphorylation at Ser807/811; ↑ ROS generation |
0–60 μM | N/A | [68] |
PC-3, LNCaP & C4-2 | Inhibit cell growth Induce apoptosis: ↑ caspase-3, caspase-8 & caspase-9 activation; ↑ PARP cleavage Induce apoptosis via DNA fragmentation: ↑ Bax & Bak proteins; ↓ Mcl-1 protein |
0–75 μM | 18.75–37.50 μM (24 h) | [69] | |
PC-3, LNCaP | Inhibit cell viability Induce autophagy: ↑ LC3-BII protein; ↓ mTOR pathway Induce apoptosis via DNA fragmentation: ↑ ROS generation |
0–40 μM | N/A | [70] | |
Head & neck squamous cancer | Cal-33 & MD-1483 | Inhibit cell growth Induce cell apoptosis and cell cycle arrest: ↓ EGFR signalling pathway; ↓ STAT3 signalling pathway; ↓ Bcl-xL & cyclin D1; ↓ phosphorylation p42/p44 MAPK & phosphorylated Akt |
0–100 μM | Cal-33: 3.80 μM (72 h) 1483: 7.44 μM (72 h) |
[71] |
Neuroblastoma | Neuro-2a | Induce apoptosis via DNA fragmentation: ↑ caspase-3, caspase-6 & caspase-9 activation; ↑ Bax protein; ↓ mitochondrial membrane potential; ↑ cytochrome c releaseInduce sub-G1 phase cell cycle arrest | 0–100 μM | 63.3 μM (72 h) | [72] |
Neuro-2a & NB41A3 | Inhibit cell viability Induce autophagy: ↑ LC3-II; ↑ PI3K/Akt/mTOR signalling pathway; ↑ Grp78; ↑ ROS generation; ↑ ERK1/2; ↑ p-ERK1Induce apoptosis via DNA fragmentation Inhibit cell migration |
0–100 μM | Neuro-2a: ~50 μM (72 h) |
[73] | |
Bladder cancer | T24 & 5637 | Inhibit cell viability and induce apoptosis: ↑ Bax protein; ↑ PARP cleavage; ↓ Bcl-2 protein Inhibit clonogenicity Induce G1 phase cell cycle arrest: ↓ cyclin D1; ↑ p21 & p27 Inhibit sphere formation capacity Inhibit cell migration & invasion: ↓ EZH2 gene expression; ↓ MMP9 Inhibit cell stemness: ↓ EZH2 gene expression; ↓ CD44 & Sox2; ↑ miR-143 overexpression |
0–72 μM | N/A | [74] |
Cancer Cell Line | Animal Model & Site of Tumour Xenograft | Dose, Duration & Route of Administration | Observation & Mechanism of Action | Efficacy on Tumour Inhibition | References |
---|---|---|---|---|---|
Breast cancer | |||||
MDA-MB-231 cells | Both flanks of athymic nude mice | 100 mg/kg/day 28 days IP |
Induce tumour growth arrest | Complete arrest of tumour growth from week 2 onwards | [32] |
MDA-MB-231 cells | Right gluteal region of athymic nude mice | 3 mg/mouse/day Three times a week 28 days IP |
Inhibit tumour progression: ↓ Ki-67; ↑ LKB1 & pAMPK; ↑ ACC phosphorylation, ↓ pS6K & 4EBP1 phosphorylation |
Tumour weight of honokiol-treated group was 0.22 g compared to control group which was 1.58 g | [33] |
MDA-MB-231-pLKO.1 & MDA-MB-231-LKB1shRNA cells | Right gluteal region of athymic nude mice | 3 mg/mouse/day Three times a week 42 days Oral gavage |
Inhibit cell stemness: ↓ Oct4, Nanog & Sox2; ↓ pSTAT3 & Ki-67 Inhibit mammosphere formation |
Decreased expression of Oct4, Nanog, Sox2 Reduce number of tumour cells showing Ki-67 & pStat3 expression |
[34] |
Colorectal cancer | |||||
RKO cells | Axilla of BALB/c nude mice | 80 mg/kg/day Treatment on days 8–11, 14–17, 21–24, 28–31 51 days IP |
Inhibit tumour growth Prolong survival of mice |
709.9% increase in tumour growth rate in honokiol-treated group compared to 1627.6% and 1408.2% in control and vehicle groups respectively | [25] |
HCT116 cells | Flank of athymic nude mice | 200 μg/kg/day + 5 Gy irradiation Once a week 21 days IP |
Inhibit tumour growth: ↓ CSC proteins → ↓ DCLK1, Sox-9, CD133 & CD44 | Significantly lower tumour weight (<800 mg) in honokiol-IR combination, (~1500 mg) in honokiol treatment group compared to (~3300 mg) in control group | [28] |
Cervical cancer | |||||
KB-8-5 cells | Athymic nu/nu nude mice (site of xenograft not stated) | 50 mg/kg Honokiol Three times a week + 20 mg/kg Paclitaxel Once a week 28 days IP (honokiol) Tail vein injection (paclitaxel) |
Suppress tumour growth: ↓ Ki-67 tissue level Induce apoptosis |
Significantly lower average tumour volume for honokiol-paclitaxel combination treatment (573.9 mm3) compared to control (2585.4 mm3) | [23] |
Lung cancer | |||||
H2030-BrM3 cells | Left ventricle of NOD/SCID mice | 2 or 10 mg/kg/day 28 days Oral gavage |
Prevent metastasis of lung cancer cells to brain | 10 mg/kg: Decrease brain metastasis for >70% | [40] |
H2030-BrM3 cells | Left lung via left ribcage of athymic nude mice | 2 or 10 mg/kg/day Five days a week 28 days Oral gavage |
Decrease lung tumour growth Inhibit metastasis to lymph node |
10 mg/kg: Significantly reduce incidence of mediastinal adenopathy, decrement of weight of mediastinal lymph node for >80%, only 2/6 mice have lymphatic metastasis | [40] |
Blood cancer | |||||
Raji cells | Back of BALB/c nude mice | 5 mg/20 g & 10 mg/20 g Treatment on days 8–12 & 15–19 20 days (Route of administration not specified) |
Inhibit cell proliferation Inhibit tumour growth |
Tumour growth of honokiol-treated mice was significantly lower (~90 cm3) compared to control mice (~270 cm3) | [31] |
HL60 cells | Inoculated intraperitoneally into SCID mice | 100 mg/kg/day Treatment on Day 1–6 47 days IP |
Prolong survival of mice | Median survival time of honokiol-treated mice are longer (37.5 days) compared to vehicle-treated mice (24.5 days) | [78] |
Pancreatic cancer | |||||
MiaPaCa cells | Pancreas of immunocompromised mice | 150 mg/kg/day 28 days IP |
Suppress tumour growth Inhibit metastasis: ↓ CXCR & SHH; ↓ NF-κB & downstream pathway Inhibit desmoplastic reaction: ↓ ECM protein; ↓ collagen I |
Significant decrease in tumour growth for honokiol-treated mice (99.6 mm3) compared to vehicle-treated mice (1361.0 mm3) | [51] |
Skin cancer | |||||
SKMEL-2 or UACC-62 cells | Right flank of athymic nude mice | 50 mg/kg Three times a week 14–54 days IP |
Decrease tumour growth | SKMEL-2: 40% reduction in tumour volume UACC-62: 50% reduction in tumour volume |
[49] |
Thyroid cancer | |||||
ARO cells | BALB/cAnN.Cg-Foxn1nu/CrlNarl mice (site of xenograft not stated) | 5 or 15 mg/kg/mouse Every three days 21 days Oral gavage |
Decrease tumour volume & tumour weight Induce apoptosis & autophagy |
Control: ~1000 mm3; 700 mg 5 mg/kg Honokiol: ~600 mm3; 400 mg 15 mg/kg Honokiol: ~400 mm3; 200 mg |
[53] |
Nasopharyngeal cancer | |||||
HNE-1 cells | Right dorsal aspect of right foot of BALB/c athymic nude mice | Active-targeting nanoparticles-loaded HK (ATNH), Non-active-targeting nanoparticles-loaded HK (NATNH), Free Honokiol (HK) 3 mg/mouse/day Every three days Euthanise 50% mice after 12 days, rest are left to observe tumour growth & survival time up to 60 days; IV |
Inhibit tumour progression, Induce apoptosis Potential inhibitor of angiogenesis & proliferation |
Efficiency in tumour delay: ATNH > NATNH > Free HK Median survival time: Control: 28.5 days Free HK: 34 days NATNH: 42.5 days ATNH: 57.5 days |
[22] |
Brain cancer | |||||
U21 cells | Right flank of athymic nude mice | 20 mg/kg Twice a week 27 days Caudal vein injection |
Inhibit tumour growth Inhibit angiogenesis |
Honokiol-treated mice have significant inhibition of tumour volume by 50.21% compared to vehicle Significantly lower microvessel present in honokiol-treated cells |
[54] |
U-87 MG cell suspension pre-treated with honokiol or vehicle for 48h | Yolk sac of Zebrafish larvae | (Concentration N/A) 3 days Injection of cells into zebrafish |
Inhibit cell proliferation Inhibit cell migration |
Reduced number of cell mass compared to vehicle-treated cells | [56] |
U-87 MG cells | Right flank near upper extremity of nude mice | 100 mg/kg/day Treatment at days 1–7 21 days IP |
Reduce tumour growth: ↓ EGFR, pSTAT3, CD133 & Nestin |
Increased number of apoptotic cells in honokiol-treated tissue, Significantly lower tumour volume & tumour weight in honokiol-treated mice | [56] |
Bone cancer | |||||
HOS cells | Dorsal area of BALB/c-nu mice | 40 mg/kg/day 7 days IP |
Reduce tumour growth Induce apoptosis & autophagy: ↑ cleaved caspase-3; ↑ LC3B-II & phosphor-ERK (ROS/ERK1/2 signalling pathway) |
Significant decrease in tumour volume & weight of honokiol-treated mice (200 mm3; 0.2 g) compared to control group (~500 mm3; 0.5 g) Increased number of TUNEL-positive cells |
[18] |
LM8-LacZ cells | Left flank of C3H/HeNCrl mice | 150 mg/kg/day 25 days; IP |
Inhibit metastasis | Mean number of micrometastases decreased significantly by 41.4% in honokiol-treated mice compared to control mice | [61] |
Oral cancer | |||||
SAS cells | Right flank of BALB/cAnN.Cg-Foxn1nu.CrlNarl nude mice | 5 mg/kg or 15 mg/kg Treatment on day 1, 4, 7, 10, 13, 16, 19, 22 35 days Oral |
Reduce tumour growth & volume | Significantly reduction in tumour growth in honokiol-treated mice 29% reduction (5 mg/kg; 21 days), 40% reduction (15 mg/kg; 21 days) 41% reduction (5 mg/kg; 35 days), 56% reduction (15 mg/kg; 35 days) |
[18] |
Prostate cancer | |||||
C4-2 cells | Bilateral tibia of BALB/c nu/nu athymic nude mice | 100 mg/kg/day 42 days IP |
Inhibit cell proliferation: ↑ Ki-67 Induce apoptosis: ↑ M-31 Inhibit angiogenesis: ↑ CD-31 |
Lower PSA value in honokiol-treated mice compared to control group | [69] |
PC-3 cells | Left & right flanks above hind limb of nude mice | 1 or 2 mg/mice Monday, Wednesday & Friday two weeks before tumour implantation and duration of experiment after implantation 77 days Oral gavage |
Inhibit tumour growth Inhibit cell proliferation Inhibit neovascularisation Induce apoptosis |
Tumour volume of honokiol-treated mice are significantly lower (~330 mm3; 1 mg), (~50 mm3; 2 mg) compared to control (~400 mm3) | [79] |
Gastric cancer | |||||
MKN45 cells | Dorsal side of BALB/c nude mice (nu/nu) | 0.5 mg/kg/day & 1.5 mg/kg/day 10 days Injection (route not stated) |
Inhibit tumour growth: ↓ GRP94 overexpression | 30% reduction in tumour volume (0.5 mg/kg) 60% reduction in tumour volume (1.5 mg/kg) Decreased accumulation of GRP94 |
[80] |
MKN45 & SCM-1 cells | Peritoneal cavity of BALB/c nude mice | 5 mg/kg Twice a week 28 days IP |
Inhibit metastasis Inhibit angiogenesis |
Honokiol inhibited STAT-3 signalling and VEGF signalling induced by calpain/SHP-1 | [81] |
Ovarian cancer | |||||
SKOV3 cells | Right axilla of BALB/c nude mice | 1 mg liposome-encapsulated honokiol/day 48 days IP |
Inhibit tumour growth Inhibit angiogenesis |
Reduction in tumour growth rate in liposome-encapsulated honokiol-treated mice by 67–70% compared to control | [66][82] |
A2780s cells | Right flank of athymic BALB/c nude mice | 10 mg/kg Lipo-Honokiol Twice a week 21 days IV |
Inhibit cancer growth Prolong survival of mice Increase intra-tumoural apoptosis Inhibit intra-tumoural angiogenesis |
Lipo-HNK treated mice have significantly smaller tumour volume (222 ± 71 mm3) compared to liposome-treated mice (1823 ± 606 mm3) and control mice (3921 ± 235 mm3) |
[66] |
A2780cp cells | Right flank of athymic BALB/c nude mice | 10 mg/kg Lipo-Honokiol Twice a week 21 days IV |
Inhibit cancer growth Prolong survival Increase intra-tumoural apoptosis Inhibit intra-tumoural angiogenesis |
Lipo-HNK treated mice have significantly smaller tumour volume (408 ± 165 mm3) compared to liposome-treated mice (2575 ± 701 mm3) and control mice (2828 ± 796 mm3) |
[66] |