体外研究
(In Vitro) | FL118 (0-200 nM; 24, 48 and 72 h ) inhibits the cell proliferation of ES-2 and SK-O-V3cells[1].FL118 (0-100 nM; 0 and 24 h) inhibits the migration of ES-2 and SK-O-V3cells[1].FL118 (0-100 nM; 48 h) affects the expression level of cytoglobin (CYGB)[1].FL118 (10 and 100 nM; 48 h) inhibits PI3K/AKT/mTOR signaling pathway, and affects the expression level of vimentin and E-cadherin in ovarian cancer cells[1].FL118 (0-100 nM; 6 and 24 h) dephosphorylates and degrades DDX5[2].FL118 (0-500 nM; 24, 48, 72 h) regulates survivin, McL-1, XIAP, cIAP2, c-MYc and mKras by regulating DDX5[2].FL118 (0-1 μM, 24 h) shows significant cytotoxic activity against the three tumor cell lines (A549, MDA-MB-231, and RM-1 cells)[3].
FL118 (0-10 nM, 48 h) increases the production of PARP cleavage, and induces apoptosis in A549[3].
FL118 (0-10 nM, 48 h) arrests A549 cells mainly at the G2/M phase[3].
Western Blot Analysis[1] | Cell Line: | ES-2 and SK-O-V3cell lines | | Concentration: | 10 and 100 nM | | Incubation Time: | 48 h | | Result: | Effectively inhibited the activation of PI3K/AKT/mTOR signaling pathway in ovarian cancer cells and also inhibited the migration of ES-2 and SK-O-V3cells. |
Cell Migration Assay[1] | Cell Line: | ES-2 and SK-O-V3cell lines | | Concentration: | 0, 10 and 100 nM | | Incubation Time: | 0 and 24 h | | Result: | Inhibited the migration of ES-2 and SK-O-V3cells dose-dependenly. |
RT-PCR[1] | Cell Line: | ES-2 and SK-O-V3cell lines | | Concentration: | 0, 10 and 100 nM | | Incubation Time: | 48 h | | Result: | Promoted CYGB expression. |
Cell Proliferation Assay[1] | Cell Line: | ES-2 and SK-O-V3cell lines | | Concentration: | 0, 1, 10, 50, 100 and 200 nM | | Incubation Time: | 24, 48 and 72 h | | Result: | Inhibited the cell proliferation of ES-2 and SK-O-V3cells time- and dose-dependently. |
Western Blot Analysis[2] | Cell Line: | SW620 and Mia Paca-2 | | Concentration: | 0, 10 and 100 nM | | Incubation Time: | 6 and 24 h | | Result: | Induced dephosphorylation of DDX5 through the ubiquitin-proteasome degradation pathway and degraded DDX5 time-dependently. |
Western Blot Analysis[2] | Cell Line: | PDAC Panc1, CRC HCT-8, SW620, Mia Paca-2, Panc-1, HCT-8 cell lines | | Concentration: | 0, 10, 100 and 500 nM | | Incubation Time: | 24, 48, 72 h | | Result: | Controled the expression of survivin, Mcl-1, XIAP, cIAP2, c-Myc and mKras by regulated
DDX5, as an upstream master regulator in cancer development and malignant networks. |
Cell Cytotoxicity Assay[3] | Cell Line: | A549, MDA-MB-231, RM-1 | | Concentration: | 0-1 μM | | Incubation Time: | 24 h | | Result: | Showed cytotoxicity in A-549 (human lung carcinoma), MDA-MB-231 (human breast carcinoma) and RM-1 (mouse prostate carcinoma), with IC50values of 8.94 ± 1.54 , 24.73 ± 13.82, and 69.19 ± 8.34 nM, respectively. |
Apoptosis Analysis[3] | Cell Line: | A549 cells | | Concentration: | 0, 2.5, 5, 10 nM | | Incubation Time: | 48 h | | Result: | Resulted in the downregulation of survivin. Increased the production of PARP cleavage in a concentration-dependent manner, which is the hallmark of apoptosis. Induced apoptosis in A549. |
Cell Cycle Analysis[3] | Cell Line: | A549 cells | | Concentration: | 0, 2.5, 5, 10 nM | | Incubation Time: | 48 h | | Result: | Increased G2/M cell population in a concentration-dependent manner, and arrested A549 cells mainly at the G2/M phase. |
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体内研究
(In Vivo) | FL118 (5 and 10 mg/kg; p.o. once a week for 20 days) inhibits antitumor activity[1].
FL118 (0-1.5 mg/kg, i.p. once every other day for five times) effectively eliminates human colon and head-and-neck tumors that acquire irinotecan or topotecan resistance[4].
FL118 (1.5 mg/kg, i.v. once) exhibits favorable pharmacokinetics profiles[4].
Pharmacokinetic Parameters of FL118 in female SCID mice[4].
| Sample | FaDu | SW620 | Plasma | | T1/2(hr) | 6.852 | 12.75 | 1.788 | | Tmax(hr) | 0.167 | 0.167 | 0.167 | | Cmax(ng/g, mL) | 115 | 158 | 43 | | AUC (hr*ng/g) | 413 | 842 | 82 | | AUC∞(hr*ng/g) | 448 | 897 | 104 | | AUC% Extrap (%) | 7.74 | 6.17 | 21.7 | | Vz (g/kg) (ml/kg) | 33052 | 30742 | 36849 | | Cl (g/hr/kg) (ml/hr/kg) | 3343 | 1671 | 14287 |
| Animal Model: | Fmale BALB/c nude mice[1] | | Dosage: | 5 and 10 mg/kg | | Administration: | Oral gavage; 5 mg/kg for once a week; 10 mg/kg for once a week; for 20 days | | Result: | Showed better antitumor activity than topotecan and dose-dependenly suppressed the growth of ES-2 tumors by upregulating the expression level of CYGB. |
| Animal Model: | SCID (severe combined immunodeficiency) mice bearing human SW620 (colon) and FaDu (head-and-neck) xenograft tumors (ten-week-old, female, 20-25 g, 5 mice per cage)[4] | | Dosage: | 0, 0.75, 1, 1.5 mg/kg | | Administration: | IP, once every other day for five times as one cycle (If tumors relapse, mice were treated with FL118 for second or third cycles) | | Result: | Eliminated human xenograft tumors that acquired irinotecan or topotecan resistance, and was also effective after multiple cycles of treatment without the generation of FL118 resistance. |
| Animal Model: | SCID (severe combined immunodeficiency) mice bearing human SW620 (colon) and FaDu SCID mice bearing human SW620 (colon) and FaDu (head-and-neck) xenograft tumors (ten-week-old, female, 20-25 g, 5 mice per cage)[4] | | Dosage: | 1.5 mg/kg | | Administration: | IV, once | | Result: | Exhibited favorable pharmacokinetics profiles. |
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