Table 2.
In vivo studies on synthetic PI3K/Akt/mTOR inhibitors in prostate cancer.
| Treatment | Animals | Model | Number of Animals | Treatment Duration | Results | Reference |
|---|---|---|---|---|---|---|
| Sapanisertib (1 mg/kg/day, oral) | Nude mice | PC3 tumor xenograft | n = 10 | 21 days | ↓PC3 xenograft growth ↓tumors weight ↑apoptosis Inactivation of mTORC 1/2 Downregulation of cyclin D1 and HIF1α |
[34] |
| Palomid 529 (100 mg/kg, s.c.) | Male CD1 athymic nude mice | PC3 or 22rv1 tumor xenograft | n = 48 | 4 weeks | ↑radiation effect ↓growth rate, tumor volume, and tumor weight ↑apoptotic cells→↓ proliferation index and the number of vessels |
[89] |
| Bicalutamide (10 mg/kg, i.p.); Ridaforolimus (0.3 mg/kg, i.p.); and Bicalutamide (10 mg/kg, i.p.) + ridaforolimus (0.3 mg/kg, i.p.) |
Male nude mice | C4-2 tumor xenograft | n = 10 | 21 days | ↓tumor growth in single agent and combination Combination →↑ antitumor activity Combination →↓ plasma PSA level |
[68] |
| Everolimus (7.5 μg/g, i.p.) | Aged Tsc1 KO mice | Mouse model of TSC1 deletion in prostate epithelium | n = 6 | 3 times/per week (for 4 weeks) | Inhibition of the mTORC1 pathway in the testis and prostate everolimus → antiproliferative effect in testis |
[90] |
| Everolimus (10 mg/kg/day, oral) | Mice | Prostate hyperplasia in PB-Rheb transgenic mice | n = 6 | Daily for 1 week | Akt Rheb overexpression → relief of Akt inhibition by PTEN haplo-insufficiency and↑ of mTORC1 level |
[91] |
| Styrene sulfonamide acid (2–10 mg/kg, i.p.) and Fingolimod (FTY720) (5 mg/kg, i.p.) |
Nude mice | PC3 tumor xenograft | n = 6 | 14 days | ↓apoptos ↓cell growth ↓tumor growth ↓mTOR/Akt pathway |
[77] |
| NSK-01105 (a sorafenib derivative) (7.5–30 mg/kg/day, oral) and Sorafenib (30 mg/kg/day, oral) |
Male BALB/c nu/nu nude mice | LNCaP and PC3 tumor xenograft | Sorafenib group in LNCaP model: (n = 4) Other groups: n = 6 |
21 days | ↑inhibition rate in both models ↓phosphorylation of ERK and mTOR ↓Akt phosphorylation ↓Bcl-2 |
[84] |
| IGFBP-3 (5 × 108 PFU in PBS, i.p.) and IGFBP-3 + IL-24 (5×108 PFU in PBS, i.p.) |
Athymic nude mice | LNCaP tumor xenograft | n = 6 | Every day (24 days) | tumor size ↑expression of PARP ↓mTOR |
[92] |
| Salinomycin (5 mg/kg; C4-2 cells: oral gavage; and LNCaP-II cells: i.p.) |
Nude male mice | LNCaP-II and C4-2 tumor xenograft | Control: n = 5 Salinomycin: n = 3 LNCaP-II: n = 5 C4-2: n = 4 |
LNCaP-II: every 3rd day until day 16 C4-2: every 2nd day until day 21 |
Salinomycin in LNCaP-II:↓ CYP17A1 and P-RPS, and ↓ tumor size Salinomycin in C4-2: ↓tumor size and ↓phospho- TSC2 |
[37] |
| Salinomycin (5 mg/kg, oral) | Nude male mice PTENpc−/− |
PC3 and LNCAP tumor xenograft | n = 2 | 21 days | ↓cytostasis ↓apoptosis ↓autophagy ↓mTORC1 activity ↓tumor growth |
[37] |
| Everolimus (10 mg/kg, i.p.) | Mice | Xenograft prostate tumor (injection of AMD1 silencing or AMD1 ectopic expression cells) | n = 3 | - | ↓AMD1 pro expression level | [70] |
| Docetaxel (5 mg/kg, i.p.); Everolimus (5 mg/kg, i.p.); and Docetaxel (5 mg/kg, i.p.) + everolimus (5 mg/kg, i.p.) |
BALB/c nude male mice | PC3 tumor xenograft | n = 4 | Twice a week (3 weeks) | ↓tumor volume with RAD + Doc | [61] |
| Apitolisib (GDC-0980) + P-GDC-0980 (5 mg/kg, i.v.) and Docetaxel + P-docetaxel (10 mg/kg, i.v) |
Nude mice | PC tumor xenograft | n = 4 | GDC-0980 + P-GDC-0980: twice per week and Docetaxel + P-docetaxel: one single dose |
↑antitumor effect | [93] |
Abbreviations: ↓ = decrease; ↑ = increase; → = leads to; AMD1 = S-adenosylmethionine decarboxylase 1; ANXA7 = annexin A7; elF4G = eukaryotic translation initiation factor 4G; ERK = extracellular signal-regulated kinases; IGFBP-3 = insulin-like growth factor binding protein-3; IL-24 = interleukine-24; LC3 = light chain 3; P-docetaxel = polymer-docetaxel; P-GDC-0980 = polymer GDC-0980; PBS = phosphate-buffered saline; PTEN = phosphatase and tensin homolog; s.c. = subcutaneous; and TSC2 = tuberous sclerosis complex 2.