Table 7.
The anticancer activities and mechanism of Asiatic acid in different cancer types.
| Asiatic acid & derivatives | Cell lines/cancer models | Mechanisms/effects observed | Cancer type | References |
|---|---|---|---|---|
| AA | HepG2 | ↓ intracellular Ca2+levels ↑ apoptosis and p53 expression |
Liver cancer | Lee et al., 2002 |
| AA | SK-MEL-2 | ↓ viability and ↑ apoptosis ↑ ROS levels and Bax but not Bcl-2 ↑ activation of caspase-3 activity |
Skin cancer | Park et al., 2005 |
| AA | HT-29 | ↑ cytotoxicity, DNA fragmentation, apoptosis, and caspase-3 activation augmenting effect of irinotecan ↓ Bcl-2 and Bcl-xL proteins ↑ apoptosis via caspase-3 activation |
Colon cancer | Bunpo et al., 2005 |
| AA | PPC-1 | ↑ caspase-dependent and independent cell death ↑ activation of caspase 2,3, & 8 but not 9 ↑ Ca2+ release and dilatation of endoplasmic reticulum |
Prostate cancer | Gurfinkel et al., 2006 |
| AA | U-87 MG | ↑ dose- and time-dependent apoptosis and necrosis ↓ mitochondrial membrane potential ↑ Ca2+ and caspase-9 and−3 |
Glioblastoma | Cho et al., 2006 |
| AA | TPA-DMBA-initiated ICR mice | ↓ NO generation and expression of iNOS and COX-2 | Skin tumor | Park et al., 2007 |
| AA | SW480 | ↓ cancer cell proliferation ↑ mitochondrial membrane permeability and cytochrome c release from mitochondria into cytosol ↑ caspase-3, 9 activity and poly(ADP-ribose) polymerase results in apoptosis |
Colon cancer | Tang et al., 2009 |
| AA | Human umbilical vein endothelial cells (HUVEC) and human brain microvascular endothelial cells (HBMEC), human glioma cells (LN18 & U87-MG) | ↓ growth and capillary tube formation ↑ apoptosis by activating caspases 3 & 9 modulates expression of apoptosis regulators Bad, survivin and pAkt-ser473 ↓ cellular and secreted VEGF levels dose-dependent antiangiogenic effect |
Gliomas | Kavitha et al., 2011 |
| AA derivatives (120) | HeLa, HepG2, BGC-823, and SKOV3 | ↓ cell growth potent than AA substitution of amide group at C-28 shows potent cytotoxicity than AA comparable to gefitinib and etoposide |
Many cancer types | Meng et al., 2012 |
| AA derivatives (5) | A549 and PC9/G | ↓ cell growth potently than AA ↓ proliferation via down-regulation of the Ras/Raf/MEK/ERK pathway and cell cycle arrest at G1/S and G2/M |
Lung cancer | Wang et al., 2013 |
| AA | HepG2 | ↑ p21WAF1/CIP1 expression but no p21WAF1/CIP1 mRNA ↑p21WAF1/CIP1 with ↓ phosphorylation (ser-146) of p21WAF1/CIP1 ↓ NDR1/2 kinase and proliferation ↑ stability of p21WAF1/CIP1 |
Liver cancer | Chen et al., 2014 |
| AA | Colon cells | ↓ IL-8 production | Colon cancer | Yan et al., 2014b |
| AA | ↓ tyrosinase mRNA expression by inhibiting microphthalmia-associated transcription factor (MITF) | Melanoma | Kwon et al., 2014 | |
| AA | A549 | ↑ miR-1290, which sensitizes cells to AA cytotoxicity & ↓ viability & cell cycle progression negatively regulates BCL2 expression |
Lung cancer | Kim et al., 2014 |
| AA | MGC-803, NCI-H460, HepG2, Hela and 7404 | anticancer drug 5-fluorouracil stronger anti-proliferative activity than AA ↑ ROS and altered anti- & pro-apoptotic proteins leading to mitochondrial dysfunction and activations of caspase-3,−9 arrested HepG2 cells in G1 stage |
Many cancer types | Li et al., 2014 |
| AA | Human GBM cell (LN18, U87MG, and U118MG) ectopic U87MG xenograft implantation in mice | ↓ cell viability, better efficacy than temozolomide at equimolar doses decreased tumor volume in mice without toxicity decreased orthotopic U87MG xenografts growth in nude mice in magnetic resonance imaging crosses blood-brain barrier induced apoptotic death by modulating the protein expression of several apoptosis regulators (caspases, Bcl2 family members, and survivin) induced ER stress (increased GRP78 and calpain, and decreased calnexin and IRE1α expression) enhanced free intra-cellular calcium, and damaged cellular organization in GBM cells |
Glioblastoma multiforme | Kavitha et al., 2015 |
| AA | HL-60 leukemia cell line cells | blocked cell growth in a dose- and time-dependent manner induced apoptosis in a dose-dependent manner downregulated anti-apoptotic proteins Bcl-2, Mcl-1 and survivin were by AA in a dose-dependent manner inhibited ERK and p38 phosphorylation in a dose-dependent manner, while JNK phosphorylation was not affected |
Blood cancer | Wu et al., 2015 |
| AA modified compounds at the C-2, C-3, C-23, and C-28 | HeLa, HepG2, B16F10, SGC7901, A549, MCF7, and PC3), larval zebrafish model | potent cytotoxic & anti-angiogenic than AA markedly better anti-tumor activities than both AA and other derivatives, with similar stability as its parent compound AA |
Many cancer types | Jing et al., 2015 |
| AA | Virtual screening, cell free medium | NF-κB inhibitory down regulators of IKKβ phosphorylation | Inflammation in cancer | Patil et al., 2015 |
| AA loaded Solid lipid nanoparticles (SLNs) | U87 MG and SVG P12 | displayed more favorable drug release profile and higher cytotoxicity cellular uptake of SLNs appear preferentially facilitated by energy-dependent endocytosis concentration-dependent apoptosis |
Brain cancer | Garanti et al., 2016 |
| Fluorinated Asiatic Acid (AA) derivatives | HeLa and HT-29 cell lines, MCF-7, Jurkat, PC-3, A375, MIA PaCa-2 and BJ HeLa cell line, non-tumor BJ human fibroblast cell line | concentration dependent antiproliferative activity than AA most active compounds have a pentameric A-ring containing an α,β-unsaturated carbonyl group ↑ cell cycle arrest in G0/G1 stage, ↑ p21(cip1/waf1) and p27(kip1) ↓ cyclin D3 and Cyclin E, ↑ caspases-8 and 3 & cleavage of PARP ↑ Bax and ↓ Bcl-2 and cleavage Bid into t-Bid extrinsic and intrinsic apoptotic pathways |
Many cancer types | Gonçalves et al., 2016 |
| AA | HepG2 | anti-proliferative activity against HepG2 | Liver cancer | Shi et al., 2016 |
| AA | SKOV3 and OVCAR-3 | ↓ 50% in the viability of cells, ↓ colony formation of cells by 25–30% cell cycle arrest at the G0/G1 phase ↑ 7- to 10-fold increase in apoptosis ↓ PI3K, Akt, and mTOR phosphorylation |
Ovarian cancer | Ren et al., 2016 |
| N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe) | SGC7901 and HGC27 human gastric cancer cells human gastric mucosa epithelial cells (GES-1) | ↓ cell proliferation dose-dependently ↑ cell cycle arrest in G0/G1 phase, blocked G1-S transition ↓ cyclin D1, CKD4, and phosphorylated retinoblastoma protein ↑ cyclin-dependent kinase inhibitor P15 ↑ apoptosis affecting Bcl-2, Bax, c-Myc, and caspase-3 ↓ migration and invasion reducing MMP-2 and 9 |
Gastric cancer | Jing et al., 2016 |
| AA | Ovarian cancer cells (A2780) | ↑ cytotoxicity by inducing apoptosis | Ovarian cancer | Sommerwerk et al., 2016 |
| AA | 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats | ↓ incidence of polyps & aberrant crypt foci ↑ antioxidants & ↓ lipid peroxidation in liver alterated activity of biotransforming enzymes & histological improvement |
Colon cancer | Siddique et al., 2017 |
| AA proline methyl ester derivative (AA-PMe) | Gastric cancer cells | ↓ STAT3 activation mediated by blockade of Janus-activated kinase 2 dose dependently regulated expression of STAT3-modulated gene products including cyclin D1, Bax, Bcl-2, c-Myc and MMP-2 and 9 |
Gastric cancer | Wang et al., 2017 |
| AA derivatives | Cancer cell lines (HepG2 and SGC7901) | compounds I2, I6, and II6 potent cytotoxic activity than that of the positive control paclitaxel in MTT assay docking shows interactions between compounds I2,I6,II6 and survivin |
Liver cancer | Meng et al., 2018 |
| AA | SVG p12 fetal glia and U87-MG grade IV glioblastoma cells under normoxic (21% O2) and hypoxia (1% O2) | cell viability, proliferation, apoptosis and wound healing cytotoxic effects on glioma cell lines and has the potential to become an alternative treatment for glioblastoma |
Glioblastoma | Thakor et al., 2017 |
| AA | Lung cancer both xenograft model in mice in vivo and in vitro | induced apoptosis and autophagy (elevated microtubule-associated protein 1 light chain 3 (LC3) and decreased p62 expression prevented mitochondrial injury, decreased expression of proliferating cell nuclear antigen |
Lung cancer | Wu et al., 2017 |