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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

Capacity to stimulate P-glycoprotein ATPase activity of verapamil and quinine hydrochloride.Abbreviation: ATPase, adenosine triphosphatase.
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f1-ijn-10-4225: Capacity to stimulate P-glycoprotein ATPase activity of verapamil and quinine hydrochloride.Abbreviation: ATPase, adenosine triphosphatase.

Mentions: Membrane vesicles were incubated with increasing concentrations of QN and verapamil (a known P-gp substrate). ATPase activity was analyzed and the results are shown in Figure 1. Verapamil can dose-dependently stimulate the ATPase activity of P-gp and was used as a positive control. We found that QN increased ATPase activity at all concentrations between 5 and 100 µM, which indicates that QN is also a substrate of P-gp. In order to quantitatively evaluate the interaction of VCR and QN with P-gp, we calculated the maximal reaction rates (Vmax) and apparent Michaelis constants (Km) using double reciprocal plots of the ATPase activity assay data.26 The Km value for verapamil was 4.38 µM, while quinine treatment resulted in a 2.42–2.86-fold increase in ATPase activity with a Km of 1.19 µM, indicating that QN has a higher affinity for P-gp than verapamil. Since the Km value of VCR is reportedly 5.9±2.5 µM,27,28 QN can effectively compete for the transporter binding sites normally occupied by the substrate VCR.


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

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

Capacity to stimulate P-glycoprotein ATPase activity of verapamil and quinine hydrochloride.Abbreviation: ATPase, adenosine triphosphatase.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-10-4225: Capacity to stimulate P-glycoprotein ATPase activity of verapamil and quinine hydrochloride.Abbreviation: ATPase, adenosine triphosphatase.
Mentions: Membrane vesicles were incubated with increasing concentrations of QN and verapamil (a known P-gp substrate). ATPase activity was analyzed and the results are shown in Figure 1. Verapamil can dose-dependently stimulate the ATPase activity of P-gp and was used as a positive control. We found that QN increased ATPase activity at all concentrations between 5 and 100 µM, which indicates that QN is also a substrate of P-gp. In order to quantitatively evaluate the interaction of VCR and QN with P-gp, we calculated the maximal reaction rates (Vmax) and apparent Michaelis constants (Km) using double reciprocal plots of the ATPase activity assay data.26 The Km value for verapamil was 4.38 µM, while quinine treatment resulted in a 2.42–2.86-fold increase in ATPase activity with a Km of 1.19 µM, indicating that QN has a higher affinity for P-gp than verapamil. Since the Km value of VCR is reportedly 5.9±2.5 µM,27,28 QN can effectively compete for the transporter binding sites normally occupied by the substrate VCR.

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