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. 2021 Jan 1;13(1):115. doi: 10.3390/cancers13010115

Table 4.

In vivo model demonstrated the ISL induced different pathway in various cancers.

Cancer Tumor Model Dose Applied Duration Effect of ISL In Vivo Ref
Breast cancer MDA-MB-231 bearing female nude mice 20 mg/kg/day
50 mg/kg/day
IP 25 days ISL inhibit angiogenesis
ISL inhibit breast cancer growth
Little influence on normal tissue
[57]
MDA-MB-231 bearing Balb/c nu/nu mice 10 mg/kg/day
20 mg/kg/day
5 times/week
Oral 38 days Anti-metastatic activities [64]
6-week-old female, MDA-MB-231 bearing BALB/c nude mice 50 mg/kg/day
100 mg/kg/day
3 times/week
IP 5 weeks Cancer growth inhibition and through downregulating AA metabolic network and the deactivation of PI3K/AKT in human breast cancer [66]
MMTV-PyMT transgenic mice 50 mg/kg/day Oral 7 weeks
(4th~11th week)
Suppress cancer growth and inhibit the metastasis via regulating miR-374a/PTEN/AKT axis
Little influence on normal tissue
[67]
MMTV-PyMT mice 50 mg/kg/day Oral 8~12 weeks
(4th~12nd or 15th week)
ISL treatment significantly limited tumor foci growth and dispersion by promoting the demethylation of WIF1 promoter [51]
4-week-old female NOD/SCID mice bearing MDA-MB-231 50 mg/kg/day Oral 4 weeks Chemosensitize breast CSCs via inhibiting the GRP78/β-catenin/ABCG2 pathway [40]
4T1-bearing nude-mouse model 25 mg/kg/2 days IP 20 days iRGD modified lipid–polymer hybrid NPs improve the efficacy of ISL in anti-breast cancer [22]
5-week-old female nude-Foxn1nu mice bearing MDA-MB-231 2.5–5 mg/mL
0.25 mL/day
Oral gavage 14~25 days Inhibit triple-negative breast cancer cell (MDA-MB-231) growth through autophagy-mediated apoptosis [69]
MCF-7aro xenograft model 50~150 ppm or
0.15~0.5% in diet
Oral in diet 13th~77th days ISL acts as a chemoprotective agent to inhibit the enzyme and transcriptional activity of CYP19 [70]
Colon 7–8 week-old male BALB/c nude mice bear HCT116 tumor 2.5 mg/kg/2days
5 mg/kg/2days
Peritumoral injection 14 days Mediate apoptotic through p62/SQSTM1 upregulation in CRC cancer [73]
6-week-old male ddY AOM induced mice 10 ppm
100 ppm
250 ppm
In drinking water 16~24 weeks Against colon cancer [134]
BALB/c male mice bearing CT26 1 mg/kg/day
5 mg/kg/day
PO
IP
15 days Inhibited the growth of tumors
ISL alleviates cisplatin-induced nephrotoxicity and
hepatotoxicity
Improved the side effects of cisplatin therapy
[75]
Male AOM-treated F344 rats 100 ppm mixed in MF basal diet Oral 4 weeks Inhibited the induction of preneoplastic aberrant crypt foci (ACF)
ISL is a promising chemopreventive agent against colon carcinogenesis
[76]
6-week-old DSS-induced colitis mice 30 mg/kg Oral 10 days Inhibited MAPK pathway and suppressed the
phosphorylation of ERK1/2 and p38, and the activation of NK-κB in colon tissue
[135]
NOD-SCID old female mice 25 mg/kg,
50 mg/kg
100 mg/kg
Oral 18~30 days observed~80 days Anti-AML via ISL direct interact with FLT3 kinase (IC50 value of 115.1 ± 4.2 nM) [41]
AML 7~8-week-old female NOD-SCID mice bearing MV4-11 cells (AML xenograft model) 25 mg/kg/day
50 mg/kg/day
100 mg/kg/day
Oral 30 days ISL significantly inhibited the MV4-11 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis [41]
Immuno-
response
6–8-week-old male and female BALB/c mice (AD-like lesion model) 1% ISL daily Oral 6th~18th (12 days) ISL significantly suppressed the DNCB-induced IgE and Th2 cytokines up-regulation [98]
DTH animal model with IKKβC46A transgenic (IKKβC46A in C57BL/6 mice) 0.75 mg/ear 24, 48, 72 h ISL inhibited T cell activation in vivo via directly binding to IKKβ Cys46 [43]
Lung Carrageenan-induced pleurisy mice model 30 mg/kg IP Twice a day (12 h) Activation of Nrf2 pathway thus decreasing oxidative stress
Inhibition of the NF-κB, MAPK and NLRP3 pathways (with high level of iNOS and COX-2) causes anti-inflammatory activities
[136]
CS-induced COPD mice 10 mg/kg
20 mg/kg
30 mg/kg
Oral Twice a day for 4 weeks ISL inhibit inflammatory and oxidative stress via the regulation of the Nrf2 and NF-κB signaling pathways [137]
LPS-induced acute lung injury (ALI) in male BALB/c mice 5 mg/kg
10 mg/kg
20 mg/kg
Intracheal
instillation
Twice a day (12 h) ISL inhibited the inflammatory of LPS-induced lung injury by activating PPAR-γ and inhibiting NF-κB activation [138]
Pulmonary metastasis model: BALB/c mouse bearing Renca cells 0.1, 0.5, 2 and 10 mg/day IP 10 days ISL prevented severe leukocytopenia caused by administration of 5-FU [139]
Lung LPS-Induced ALI mouse model in C57BL/6 mice 30 mg/kg IP A single dose ISL treatment significantly alleviated lung injury in LPS-induced ALI mice via activating AMPK/Nrf2/ARE signaling and inhibited LPS-induced NLRP3 and NF-κB pathway [86]
6~8-week-old C57BL/6 mice (Influenza virus infected model) 10 mg/kg IP 18 days ISL is a dual PPARγ and Nrf2 agonist with antiviral and anti-inflammatory properties that protect against influenza virus infection [87]
6-week-old Athymic nude mice bearing NCI-H1975 cells 1 mg/kg
5 mg/kg
IP Three times per week, 12 days ISL suppresses NSCLC cell growth by directly targeting wild type or mutant EGFR.
Anticancer effects of ISL in NSCLC cells modulated the EGFR signaling through downstream AKT and ERK1/2
[42]
Induce tracheal relaxation model in male Hartley guinea-pigs 5 mg/kg
10 mg/kg
20 mg/kg
IG
intraduodenal
A single dose ISL activated the cGMP/PKG signaling cascade through PKG-dependent mechanism and thus to tracheal relaxation [89]
Melanoma 8-week-old immunocompromised mice bearing A2058 20 mg/kg IP
every other days
42 days ISL may inhibit the proliferation of melanoma cells by suppressing miR-301b and inducing its target LRIG1 [99]
6~8-week-old male C57BL/6 mice bearing B16F0 melanoma cells 15 μg/mL Oral 48 h ISL-induced differentiation of
B16F0 cells accompanied increased ROS formation
[104]
4~5-week-old female SCID mice bearing U266 and male BABL/c bearing MPC-11 tumor 100 μg/kg/day 200 μg/kg/day IP 15~20 days ISl mediated IL-6 signaling [105]
HCC 4~5w-week-old female BALB/c- mice bearing Hep3B cells 50 mg/kg/day IP 3 weeks ISL can prevent HCC tumorigenesis and metastasis through suppressing cyclin D1 and PI3K/AKT pathway [108]
4-week-old male athymic BALB/c nude mice bearing HepG2 10 mg/kg IP A single dose The effects of ISL on radiosensitization via Nrf2⇩-Keap1⇩ pathway [140]
Prostate cancer 6-week-old male BALB/c nude mice bearing PC-3 25 mg/kg/day
50 mg/kg/day
IP ~28 days IISL modulates cyclin B1–CDK1 for G2/M arrest and apoptosis [114]
Ovary cancer 6-week-old female athymic nude mice were intraperitoneally injected SKOV3 cells 12.5 mg/kg
25 mg/kg
IP
every other days
3 weeks ISL at a noncytotoxic concentration was able to antagonize EMT
ISL blocks ovarian cancer EMT by interfering with the TGF-pathway
[79]
Gastric cancer Xenograft NOD/SCID mice bearing EBV(+) or EBV(−) human gastric carcinoma (SNU719 or MKN74) 30 mg/kg/day Oral 2 weeks ISL have anti-tumor effects through up-regulating the expressions of p53, Bax, and Puma and the cleaved forms of Caspase-3 and -9 and Parp protein [124]
Osteosarco-ma 5-week-old female NOD-SCID mice bearing Saos-2 50 mg/kg/day Oral gavage 56 days ISL inhibit cell proliferation and induce the cell apoptosis via deactivating the PI3K/AKT signaling pathway [128]
Oral cancer 5–6 week-old nude mice (BALB/c nu/nu mice) bearing OSCC-CSCs 5 mg/kg/day Oral
gavage
20 days ISL-mediated reduction of GRP78 in OSCC-CSCs played a critical role [131]