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] |