Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells.

Silkworm cocoon was recorded to cure carbuncle in the Compendium of Materia Medica. Previous studies have demonstrated that the supplemental silk protein sericin exhibits anticancer activity. In the present study, we investigated the effects of silk fibroin peptide (SFP) extracted from silkworm cocoons against human lung cancer cells in vitro and in vivo and its possible anticancer mechanisms. SFP that we prepared had high content of glycine (~ 30%) and showed a molecular weight of ~ 10 kDa. Intragastric administration of SFP (30 g/kg/d) for 14 days did not affect the weights, vital signs, routine blood indices, and blood biochemical parameters in mice. MTT assay showed that SFP dose-dependently inhibited the growth of human lung cancer A549 and H460 cells in vitro with IC50 values of 9.921 and 9.083 mg/mL, respectively. SFP also dose-dependently suppressed the clonogenic activity of the two cell lines. In lung cancer H460 xenograft mice, intraperitoneal injection of SFP (200 or 500 mg/kg/d) for 40 days significantly suppressed the tumor growth, but did not induce significant changes in the body weight. We further examined the effects of SFP on cell cycle and apoptosis in H460 cells using flow cytometry, which revealed that SFP-induced cell cycle arrest at the S phase, and then promoted cell apoptosis. We demonstrated that SFP (20-50 mg/mL) dose-dependently downregulates Bcl-2 protein expression and upregulates Bax protein in H460 cells during cell apoptosis. The results suggest that SFP should be studied further as a novel therapeutic agent for the treatment of lung cancer.

Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors.

AIM: To evaluate the single- and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors. METHODS: In single-dose pharmacokinetic study, 16 patients were administered VSLI (1.5, 2.0, or 2.3 mg·m(-2)) through intravenous infusion. Another 6 patients receiving vincristine sulfate (VCR, 2.0 mg) were taken as the control. In multiple-dose pharmacokinetic study, 12 patients were administered VSLI (1.5 or 1.8 mg·m(-2)) through intravenous infusion weekly for 4 consecutive weeks. The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: After intravenous infusion of the single dose of VSLI, the plasma concentrations were characterized by bi-exponential decline curves. No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups. Compared with the patients receiving VCR, the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC), and a decrease in plasma clearance rates. On the 4th cycle in the multiple-dose study, the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ). The calculated pharmacokinetic parameters from the subjects in the multiple- and single-dose (1.5 mg·m(-2)) groups had no significant differences. Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR, VSLI-associated adverse events were similar to those associated with conventional VCR. CONCLUSION: VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR. No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks. VSLI was generally tolerated in the subjects. The phase II dose of VSLI may be recommended as 4 doses of 1.5 mg·m(-2) for treatment of patients with advanced solid tumors.

Pharmacokinetics of panaxatrol disuccinate sodium, a novel anti-cancer drug from Panax notoginseng, in healthy volunteers and patients with advanced solid tumors.

AIM: To evaluate single-dose and multiple-dose pharmacokinetics of panaxatrol disuccinate sodium in healthy volunteers and patients with advanced solid tumors. METHODS: In the single-dose pharmacokinetic study, 27 healthy volunteers received panaxatrol disuccinate sodium in three doses (70, 100, and 140 mg·m⁻²). In the multiple-dose pharmacokinetic study, Panaxatrol disuccinate sodium was administered to 8 patients at 100 mg·m⁻² daily in a 30-day continuous intravenous injection. Determination of the panaxatrol disuccinate sodium plasma concentration was performed by an LC-MS method. The pharmacokinetic analysis system - Drug and Statistics (DAS) - was applied to assess plasma panaxatrol disuccinate sodium concentration-time data. RESULTS: After a single intravenous dose of 70, 100, or 140 mg·m⁻² was administered to subjects, panaxatrol disuccinate sodium distributed broadly, and the plasma concentration of panaxatrol disuccinate sodium declined rapidly. No significant differences were observed in the main pharmacokinetic parameters among the three dosing groups, including AUC(0-t), MRT(0-t), VRT(0-t), t(1/2Z), CL(z/F), V(z/F), and C0 (P>0.05). In the multiple-dose pharmacokinetic study, the mean steady-state peak concentration (C(max)), trough concentration (C(min)), average concentration (C(av)), mean steady state AUC (AUC(ss)) and the degree of fluctuation were 13.96±15.48 mg·L⁻¹, 0.18±0.29 mg·L⁻¹, 0.15±0.29 mg·L⁻¹, 3.58±6.94 mg·L⁻¹·h, and 148.00±117.18, respectively. At any given dose of panaxatrol disuccinate sodium, interindividual variability in the pharmacokinetic parameters was obvious. CONCLUSION: The effect of the dose level on single-dose pharmacokinetics of panaxatrol disuccinate sodium was not significant. No accumulation was observed with exposure to 100 mg·m⁻² panaxatrol disuccinate sodium in the 30-day continuous intravenous injection. All subjects were evaluated for tolerability throughout the study. Thus, the phase II dose of panaxatrol disuccinate sodium may be considered to be 100 mg·m⁻² for a 30-day continuous intravenous injection to treat patients with advanced solid tumors.

[Effect of TTRAP expression on apoptosis induced by hydroquinone in HL-60 cells in vitro.].

OBJECTIVE: To study the effect of TTRAP expression on apoptosis induced by hydroquinone in HL-60 cells in vitro, and explore the relationship between TTRAP expression and the apoptosis. METHODS: Apoptotic and necrotic rate was examined by flow cytometer with Anti-AnnexinV/FITC Plus PI staining. The mRNA expression of TTRAP was detected by RT-PCR. The differences in different treated groups were compared. RESULTS: After different concentrations of hydroquinone to the cells for 0, 4, 8, 12 h culture, were added, the cell apoptotic rate in different concentrations of hydroquinone groups was significantly higher than that in blank control groups. The optimal concentration of hydroquinone was 200 micromol/L, lasting for 8 h. When it was 250 micromol/L, the necrotic rate increased significantly. The apoptosis induced by hydroquinone was associated with the culture time at the concentration of 200 micromol/L, and the peak apoptotic time was 8 h. Then the apoptotic rate decreased and necrotic rate increased. Furthermore, with the concentrations of hydroquinone increased and time lasted for 8 h, the apoptotic rate of cells increased, the amount of TTRAP expression in the mRNA level also increased accordingly. When the concentrations of hydroquinone was above 250 micromol/L, necrotic rate increased sharply, and the amount of TTRAP expression decreased. CONCLUSION: Hydroquinone could induce apoptosis of HL-60 cells. The up-regulation of TTRAP expression may promote hydroquinone to induce HL-60 cells to go into apoptosis in vitro with dose-effect and time-effect relationship.

[Redox modulation of large conductance calcium-activated potassium channels in rat cultured trigeminal ganglion neurons].

AIM: To observe redox modulation of ion channel in trigeminal ganglion neurons by oxidants and reducing agents. METHODS: The effects of oxidants and reducing agents on maxi-conductance calcium-activated potassium channel in cultured rat trigeminal ganglion neurons by using whole-cell patch-clamp technique. RESULTS: Methionine-specific oxidant chloramine-T (Ch-T) 1 mmol/L slightly increased the current amplitude and this enhancement did not antagonized by DTT. In contrast, cysteine-specific reagent 5, 5'-dithio-bis(2-nitrobenzoic acid) (DTNB) 500 micromol/L significantly decreased current amplitude of BK(Ca) channels. The effect was reversed by the reducing agent 2 mmol/L 1, 4-dithio-DL-threitol (DTT). CONCLUSION: Reactive oxygen species were definitely involved in regulation of native neuronal function via redox modulation of BK(Ca) channels, which are suggested to play compensatory roles under oxidative stress-related conditions.