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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

Therapeutic efficacy in A549/T tumor-bearing mice (n=5 per group).Notes: Eight groups of drugs and formulations were injected intravenously into the lateral tail vein of each mouse at a VCR dose of 1.0 mg/kg on days 0, 3, 6, and 9. (A) Tumor growth curves for different groups with various treatments. (B) Photographs of the tumors collected from different groups of mice at the end of treatments (day 21). (C) Change in average body weight in mice with various treatments. (D) Average weights of tumors in each treatment group on day 21. The standard deviation is presented in error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; QNL, QN liposome; L1:2, VCR liposome + QN liposome =1:2; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
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f7-ijn-10-4225: Therapeutic efficacy in A549/T tumor-bearing mice (n=5 per group).Notes: Eight groups of drugs and formulations were injected intravenously into the lateral tail vein of each mouse at a VCR dose of 1.0 mg/kg on days 0, 3, 6, and 9. (A) Tumor growth curves for different groups with various treatments. (B) Photographs of the tumors collected from different groups of mice at the end of treatments (day 21). (C) Change in average body weight in mice with various treatments. (D) Average weights of tumors in each treatment group on day 21. The standard deviation is presented in error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; QNL, QN liposome; L1:2, VCR liposome + QN liposome =1:2; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.

Mentions: In vivo antitumor tests were performed using A549/T tumor-bearing nude mice. Considering the severe neurotoxicity of VCR, we set the dose of VCR at 1.0 mg/kg. The antitumor efficacy of the treatments was assessed by measuring tumor volume and tumor weight after intravenous injection. Figure 7A shows the changes of A549/T tumor volume after the various treatments. In the control group, the tumors grew rapidly, and the tumor volume was over 3,000 mm3 after 20 days. Both FQN and QN liposomes barely inhibited tumor progression, confirming that QN was ineffective against A549/T tumors. Only weak inhibition of tumor growth was observed in the FVCR group and in the VCR liposome group, due to drug resistance. It should be noted that tumor growth was significantly inhibited by all formulations that contained both VCR and QN (F1:2, L1:2, VQL1:2). The tumor growth inhibition in the F1:2, L1:2, and VQL1:2 groups was 2.42-fold, 2.91-fold, and 5.38-fold greater, respectively, than in the control group. VQL1:2 treatment had the highest antitumor activity, and this is in agreement with the in vitro cytotoxicity data. At the end of the experiment, all tumors were removed and weighed. A summary of the significance levels of tumor weight in the various groups is shown in Figure 7B and D. The VQL1:2 group had the smallest tumor size.


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

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

Therapeutic efficacy in A549/T tumor-bearing mice (n=5 per group).Notes: Eight groups of drugs and formulations were injected intravenously into the lateral tail vein of each mouse at a VCR dose of 1.0 mg/kg on days 0, 3, 6, and 9. (A) Tumor growth curves for different groups with various treatments. (B) Photographs of the tumors collected from different groups of mice at the end of treatments (day 21). (C) Change in average body weight in mice with various treatments. (D) Average weights of tumors in each treatment group on day 21. The standard deviation is presented in error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; QNL, QN liposome; L1:2, VCR liposome + QN liposome =1:2; 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

f7-ijn-10-4225: Therapeutic efficacy in A549/T tumor-bearing mice (n=5 per group).Notes: Eight groups of drugs and formulations were injected intravenously into the lateral tail vein of each mouse at a VCR dose of 1.0 mg/kg on days 0, 3, 6, and 9. (A) Tumor growth curves for different groups with various treatments. (B) Photographs of the tumors collected from different groups of mice at the end of treatments (day 21). (C) Change in average body weight in mice with various treatments. (D) Average weights of tumors in each treatment group on day 21. The standard deviation is presented in error bars.Abbreviations: VCR, vincristine; QN, quinine; FVCR, free vincristine; FQN, free quinine; F1:2, free vincristine + free quinine =1:2; VCRL, VCR liposome; QNL, QN liposome; L1:2, VCR liposome + QN liposome =1:2; VQL1:2, VCR and QN codelivery liposome with a ratio of 1:2.
Mentions: In vivo antitumor tests were performed using A549/T tumor-bearing nude mice. Considering the severe neurotoxicity of VCR, we set the dose of VCR at 1.0 mg/kg. The antitumor efficacy of the treatments was assessed by measuring tumor volume and tumor weight after intravenous injection. Figure 7A shows the changes of A549/T tumor volume after the various treatments. In the control group, the tumors grew rapidly, and the tumor volume was over 3,000 mm3 after 20 days. Both FQN and QN liposomes barely inhibited tumor progression, confirming that QN was ineffective against A549/T tumors. Only weak inhibition of tumor growth was observed in the FVCR group and in the VCR liposome group, due to drug resistance. It should be noted that tumor growth was significantly inhibited by all formulations that contained both VCR and QN (F1:2, L1:2, VQL1:2). The tumor growth inhibition in the F1:2, L1:2, and VQL1:2 groups was 2.42-fold, 2.91-fold, and 5.38-fold greater, respectively, than in the control group. VQL1:2 treatment had the highest antitumor activity, and this is in agreement with the in vitro cytotoxicity data. At the end of the experiment, all tumors were removed and weighed. A summary of the significance levels of tumor weight in the various groups is shown in Figure 7B and D. The VQL1:2 group had the smallest tumor size.

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