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Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.

Xu Y, Qiu L - Int J Nanomedicine (2015)

Bottom Line: The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice.The results of this in vivo study indicated that VQL could reverse VCR resistance.In addition, it reduced tumor volume 5.4-fold when compared with other test groups.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.

ABSTRACT
The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Cellular uptake of VCR for various groups in (A) A549/T, (B) MCF-7/A, and (C) HCT-8/V cells.Notes: Formulations were added at a VCR concentration of 50 µg/mL, and then incubated for 1, 2, 4, and 8 hours at 37°C. The data represent the mean ± standard deviation of three replicates.Abbreviations: VCR, vincristine; FVCR, free vincristine; F1:1, free vincristine + free quinine =1:1; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
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f5-ijn-10-4225: Cellular uptake of VCR for various groups in (A) A549/T, (B) MCF-7/A, and (C) HCT-8/V cells.Notes: Formulations were added at a VCR concentration of 50 µg/mL, and then incubated for 1, 2, 4, and 8 hours at 37°C. The data represent the mean ± standard deviation of three replicates.Abbreviations: VCR, vincristine; FVCR, free vincristine; F1:1, free vincristine + free quinine =1:1; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.

Mentions: The accumulation of VCR in MCF-7/A, HCT-8/V, and A549/T cells was determined quantitatively by HPLC. As shown in Figure 5, the uptake of free VCR in MCF-7/A cells and HCT-8/V cells began to decline after 4 hours of incubation, indicating that the MDR proteins overexpressed in these cells may pump the drugs out of the cells. When FQN was coadministered, uptake of VCR increased over the entire experimental period. More notably, the intracellular concentration of VCR in the VQL group gradually improved with extended incubation time. The intracellular concentration was also apparently higher than in the other groups, especially in MCF-7/A cells and HCT-8/V cells expressing high levels of P-gp. These results demonstrated that the efflux of VCR in resistant cancer cells was inhibited to some extent by liposome-encapsulated QN. These results are consistent with the cytotoxicity assessment.


Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.

Xu Y, Qiu L - Int J Nanomedicine (2015)

Cellular uptake of VCR for various groups in (A) A549/T, (B) MCF-7/A, and (C) HCT-8/V cells.Notes: Formulations were added at a VCR concentration of 50 µg/mL, and then incubated for 1, 2, 4, and 8 hours at 37°C. The data represent the mean ± standard deviation of three replicates.Abbreviations: VCR, vincristine; FVCR, free vincristine; F1:1, free vincristine + free quinine =1:1; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494179&req=5

f5-ijn-10-4225: Cellular uptake of VCR for various groups in (A) A549/T, (B) MCF-7/A, and (C) HCT-8/V cells.Notes: Formulations were added at a VCR concentration of 50 µg/mL, and then incubated for 1, 2, 4, and 8 hours at 37°C. The data represent the mean ± standard deviation of three replicates.Abbreviations: VCR, vincristine; FVCR, free vincristine; F1:1, free vincristine + free quinine =1:1; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; L1:1, VCR liposome + QN liposome =1:1; L1:2, VCR liposome + QN liposome =1:2; VQL1:1, VCR and QN codelivery liposome with a ratio of 1:1; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
Mentions: The accumulation of VCR in MCF-7/A, HCT-8/V, and A549/T cells was determined quantitatively by HPLC. As shown in Figure 5, the uptake of free VCR in MCF-7/A cells and HCT-8/V cells began to decline after 4 hours of incubation, indicating that the MDR proteins overexpressed in these cells may pump the drugs out of the cells. When FQN was coadministered, uptake of VCR increased over the entire experimental period. More notably, the intracellular concentration of VCR in the VQL group gradually improved with extended incubation time. The intracellular concentration was also apparently higher than in the other groups, especially in MCF-7/A cells and HCT-8/V cells expressing high levels of P-gp. These results demonstrated that the efflux of VCR in resistant cancer cells was inhibited to some extent by liposome-encapsulated QN. These results are consistent with the cytotoxicity assessment.

Bottom Line: The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice.The results of this in vivo study indicated that VQL could reverse VCR resistance.In addition, it reduced tumor volume 5.4-fold when compared with other test groups.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.

ABSTRACT
The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus