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In Vitro and In Vivo Tumor Growth Inhibition by Glutathione Disulfide Liposomes

View Article: PubMed Central - PubMed

ABSTRACT

Glutathione disulfide (GSSG) is an endogenous peptide and the oxidized form of glutathione. The impacts of GSSG on cell function/dysfunction remain largely unexplored due to a lack of method to specifically increase intracellular GSSG. We recently developed GSSG liposomes that can specifically increase intracellular GSSG. The increase affected 3 of the 4 essential steps (cell detachment, migration, invasion, and adhesion) of cancer metastasis in vitro and, accordingly, produced a significant inhibition of cancer metastasis in vivo. In this investigation, the effect of GSSG liposomes on cancer growth was investigated with B16-F10 and NCI-H226 cells in vitro and with B16-F10 cells in C57BL/6 mice in vivo. Experiments were conducted to elucidate the effect on cell death through promotion of apoptosis and the effect on the cell cycle. The in vivo results with C57BL/6 mice implanted subcutaneously with B16-F10 cells showed that GSSG liposomes retarded tumor proliferation more effectively than that of dacarbazine, a chemotherapeutic drug for the treatment of melanoma. The GSSG liposomes by intravenous injection (GLS IV) and GSSG liposomes by intratumoral injection (GLS IT) showed a tumor proliferation retardation of 85% ± 5.7% and 90% ± 3.9%, respectively, compared with the phosphate-buffered saline (PBS) control group. The median survival rates for mice treated with PBS, blank liposomes, aqueous GSSG, dacarbazine, GLS IV, and GLS IT were 7, 7, 7.5, 7.75, 11.5, and 16.5 days, respectively. The effective antimetastatic and antigrowth activities warrant further investigation of the GSSG liposomes as a potentially effective therapeutic treatment for cancer.

No MeSH data available.


Related in: MedlinePlus

Effects on subcutaneous tumor growth by different treatments. C57BL/6 mice (4 mice/cage) were inoculated with B16-F10 cells (2 millions in 50 µL PBS) subcutaneously. Treatments started when subcutaneous tumors reached an average volume of 25 µL. Various treatments included control 1 (phosphate-buffered saline [PBS]), control 2 (BLS): blank liposomes, control 3 (GAQ): GSSG aqueous solution (0.48 g/kg), positive control (D50): dacarbazine (50 mg/kg), GSSG liposomes by IV injection (0.48 g/kg) (GLS IV), and GSSG liposomes by intratumoral injection (0.48 g/kg) (GLS IT). (A) Plots of tumor size vs experimental time (days) derived from different treatments. (B) Kaplan-Meier survival curves derived from different treatments. The survival rates of the GLS IV group and GLS IT group were significantly increased compared with the PBS group (P = .0001, .0001), BLS group (P < .0001, <.0001), GAQ group (P = .0002, .0002), and D50 group (P = .0002, <.0001). The GLS IT group also showed a significant increase in the survival rate than the GLS IV group (P = .0028); P value was calculated using the log-rank test.
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f8-10.1177_1179064417696070: Effects on subcutaneous tumor growth by different treatments. C57BL/6 mice (4 mice/cage) were inoculated with B16-F10 cells (2 millions in 50 µL PBS) subcutaneously. Treatments started when subcutaneous tumors reached an average volume of 25 µL. Various treatments included control 1 (phosphate-buffered saline [PBS]), control 2 (BLS): blank liposomes, control 3 (GAQ): GSSG aqueous solution (0.48 g/kg), positive control (D50): dacarbazine (50 mg/kg), GSSG liposomes by IV injection (0.48 g/kg) (GLS IV), and GSSG liposomes by intratumoral injection (0.48 g/kg) (GLS IT). (A) Plots of tumor size vs experimental time (days) derived from different treatments. (B) Kaplan-Meier survival curves derived from different treatments. The survival rates of the GLS IV group and GLS IT group were significantly increased compared with the PBS group (P = .0001, .0001), BLS group (P < .0001, <.0001), GAQ group (P = .0002, .0002), and D50 group (P = .0002, <.0001). The GLS IT group also showed a significant increase in the survival rate than the GLS IV group (P = .0028); P value was calculated using the log-rank test.

Mentions: The in vivo effect of GSSG liposomes on tumor growth was investigated with a murine melanoma model using female C57BL/6 mice as reported by Wack and colleagues.9 The inoculated subcutaneous tumors reached a volume of 25 mm3 in about 7 days when the treatment started. As shown in Figure 8A, tumors grew rapidly in mice treated with PBS (control 1), BLS (control 2), or GAQ (control 3) and reached a volume of 2000 mm3 in about 5 days after the treatment started. No significant difference was observed for tumor growth rates with the 3 controls. Dacarbazine at 50 mg/kg (D50) was used as a positive control. Dacarbazine is one of the drugs used for the treatment of melanoma27 and was investigated for its effect on the growth of subcutaneously implanted melanoma by Wack and colleagues.9 Tumor growth was slowed significantly in mice in the positive control group (D50) compared with each of the 3 control groups after 5-day treatment (Student t test, P < .05). However, tumors grew even more slowly in mice treated with either GSSG liposomes by IV injection (GLS IV) or GSSG liposomes by IT injection (GLS IT) (Student t test, P < .01). After a 7-day treatment, tumor size was significantly smaller in mice of the GLS IT group compared with those in the GLS IV group (Student t test, P < .001). The GLS IV and GLS IT groups showed a tumor proliferation retardation rate of 85% ± 5.7% and 90% ± 3.9%, respectively, compared with the PBS control group on day 6, which was the termination date of the control group. Only 43% ± 17.4% proliferation retardation was observed for the dacarbazine positive control (D50) on day 6. A university pathologist conducted a pathological examination of liver, heart, kidney, brain, lung, intestine, and stomach at the end of the in vivo experiment. No sign of toxicity was observed for the organs examined (data not shown).


In Vitro and In Vivo Tumor Growth Inhibition by Glutathione Disulfide Liposomes
Effects on subcutaneous tumor growth by different treatments. C57BL/6 mice (4 mice/cage) were inoculated with B16-F10 cells (2 millions in 50 µL PBS) subcutaneously. Treatments started when subcutaneous tumors reached an average volume of 25 µL. Various treatments included control 1 (phosphate-buffered saline [PBS]), control 2 (BLS): blank liposomes, control 3 (GAQ): GSSG aqueous solution (0.48 g/kg), positive control (D50): dacarbazine (50 mg/kg), GSSG liposomes by IV injection (0.48 g/kg) (GLS IV), and GSSG liposomes by intratumoral injection (0.48 g/kg) (GLS IT). (A) Plots of tumor size vs experimental time (days) derived from different treatments. (B) Kaplan-Meier survival curves derived from different treatments. The survival rates of the GLS IV group and GLS IT group were significantly increased compared with the PBS group (P = .0001, .0001), BLS group (P < .0001, <.0001), GAQ group (P = .0002, .0002), and D50 group (P = .0002, <.0001). The GLS IT group also showed a significant increase in the survival rate than the GLS IV group (P = .0028); P value was calculated using the log-rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5392016&req=5

f8-10.1177_1179064417696070: Effects on subcutaneous tumor growth by different treatments. C57BL/6 mice (4 mice/cage) were inoculated with B16-F10 cells (2 millions in 50 µL PBS) subcutaneously. Treatments started when subcutaneous tumors reached an average volume of 25 µL. Various treatments included control 1 (phosphate-buffered saline [PBS]), control 2 (BLS): blank liposomes, control 3 (GAQ): GSSG aqueous solution (0.48 g/kg), positive control (D50): dacarbazine (50 mg/kg), GSSG liposomes by IV injection (0.48 g/kg) (GLS IV), and GSSG liposomes by intratumoral injection (0.48 g/kg) (GLS IT). (A) Plots of tumor size vs experimental time (days) derived from different treatments. (B) Kaplan-Meier survival curves derived from different treatments. The survival rates of the GLS IV group and GLS IT group were significantly increased compared with the PBS group (P = .0001, .0001), BLS group (P < .0001, <.0001), GAQ group (P = .0002, .0002), and D50 group (P = .0002, <.0001). The GLS IT group also showed a significant increase in the survival rate than the GLS IV group (P = .0028); P value was calculated using the log-rank test.
Mentions: The in vivo effect of GSSG liposomes on tumor growth was investigated with a murine melanoma model using female C57BL/6 mice as reported by Wack and colleagues.9 The inoculated subcutaneous tumors reached a volume of 25 mm3 in about 7 days when the treatment started. As shown in Figure 8A, tumors grew rapidly in mice treated with PBS (control 1), BLS (control 2), or GAQ (control 3) and reached a volume of 2000 mm3 in about 5 days after the treatment started. No significant difference was observed for tumor growth rates with the 3 controls. Dacarbazine at 50 mg/kg (D50) was used as a positive control. Dacarbazine is one of the drugs used for the treatment of melanoma27 and was investigated for its effect on the growth of subcutaneously implanted melanoma by Wack and colleagues.9 Tumor growth was slowed significantly in mice in the positive control group (D50) compared with each of the 3 control groups after 5-day treatment (Student t test, P < .05). However, tumors grew even more slowly in mice treated with either GSSG liposomes by IV injection (GLS IV) or GSSG liposomes by IT injection (GLS IT) (Student t test, P < .01). After a 7-day treatment, tumor size was significantly smaller in mice of the GLS IT group compared with those in the GLS IV group (Student t test, P < .001). The GLS IV and GLS IT groups showed a tumor proliferation retardation rate of 85% ± 5.7% and 90% ± 3.9%, respectively, compared with the PBS control group on day 6, which was the termination date of the control group. Only 43% ± 17.4% proliferation retardation was observed for the dacarbazine positive control (D50) on day 6. A university pathologist conducted a pathological examination of liver, heart, kidney, brain, lung, intestine, and stomach at the end of the in vivo experiment. No sign of toxicity was observed for the organs examined (data not shown).

View Article: PubMed Central - PubMed

ABSTRACT

Glutathione disulfide (GSSG) is an endogenous peptide and the oxidized form of glutathione. The impacts of GSSG on cell function/dysfunction remain largely unexplored due to a lack of method to specifically increase intracellular GSSG. We recently developed GSSG liposomes that can specifically increase intracellular GSSG. The increase affected 3 of the 4 essential steps (cell detachment, migration, invasion, and adhesion) of cancer metastasis in vitro and, accordingly, produced a significant inhibition of cancer metastasis in vivo. In this investigation, the effect of GSSG liposomes on cancer growth was investigated with B16-F10 and NCI-H226 cells in vitro and with B16-F10 cells in C57BL/6 mice in vivo. Experiments were conducted to elucidate the effect on cell death through promotion of apoptosis and the effect on the cell cycle. The in vivo results with C57BL/6 mice implanted subcutaneously with B16-F10 cells showed that GSSG liposomes retarded tumor proliferation more effectively than that of dacarbazine, a chemotherapeutic drug for the treatment of melanoma. The GSSG liposomes by intravenous injection (GLS IV) and GSSG liposomes by intratumoral injection (GLS IT) showed a tumor proliferation retardation of 85% &plusmn; 5.7% and 90% &plusmn; 3.9%, respectively, compared with the phosphate-buffered saline (PBS) control group. The median survival rates for mice treated with PBS, blank liposomes, aqueous GSSG, dacarbazine, GLS IV, and GLS IT were 7, 7, 7.5, 7.75, 11.5, and 16.5 days, respectively. The effective antimetastatic and antigrowth activities warrant further investigation of the GSSG liposomes as a potentially effective therapeutic treatment for cancer.

No MeSH data available.


Related in: MedlinePlus