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Nanomicellar Formulation of Clotrimazole Improves Its Antitumor Action toward Human Breast Cancer Cells.

Marcondes MC, Fernandes AC, Itabaiana I, de Souza RO, Sola-Penna M, Zancan P - PLoS ONE (2015)

Bottom Line: We found that nCTZ was more efficient than sCTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes.This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism.Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Oncobiologia Molecular (LabOMol), Departamento de Biotecnologia Farmacêutica (BioTecFar), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.

ABSTRACT

Background: Although demonstrated as a selective anticancer drug, the clinical use of clotrimazole (CTZ) is limited due to its low solubility in hydrophilic fluids. Thus, we prepared a water-soluble nanomicellar formulation of CTZ (nCTZ) and tested on the human breast cancer cell line MCF-7 biology.

Methodology/principal findings: CTZ was nanoencapsulated in tween 80 micelles, which generated nanomicelles of, approximately, 17 nm of diameter. MCF-7 cells were treated with nCTZ and unencapsulated DMSO-solubilized drug (sCTZ) was used for comparison. After treatment, the cells were evaluated in terms of metabolism, proliferation, survival and structure. We found that nCTZ was more efficient than sCTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes. Moreover, this increased activity was also observed for lactate production, intracellular ATP content, ROS production and antioxidant potential. As a consequence, nCTZ-treated MCF-7 cells displayed alterations to the plasma membrane, mitochondria and the nucleus. Finally, nCTZ induced both apoptosis and necrosis in MCF-7 cells.

Conclusions/significance: MCF-7 cells are more sensible to nCTZ than to sCTZ. This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism. Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine.

No MeSH data available.


Related in: MedlinePlus

FACS analyses of MCF-7 cells treated with nanomicellar CTZ.The experimental procedures are described in Materials and Methods. Panel A: non-treated control cells. Panel B: MCF-7 cells treated with 50 μM nCTZ. Panel C: MCF-7 cells treated with 100 μM nCTZ. The percentage of cells in each quadrant is given.
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pone.0130555.g009: FACS analyses of MCF-7 cells treated with nanomicellar CTZ.The experimental procedures are described in Materials and Methods. Panel A: non-treated control cells. Panel B: MCF-7 cells treated with 50 μM nCTZ. Panel C: MCF-7 cells treated with 100 μM nCTZ. The percentage of cells in each quadrant is given.

Mentions: Membrane cell damage and nuclear condensation suggest that both necrosis and apoptosis are occurring as a result of nCTZ treatment. Therefore, we evaluated the PI and annexin V staining of MCF-7 cells treated for 24 hours with 50 μM or 100 μM nCTZ by FACS analysis. These experiments revealed that the annexin V staining of MCF-7 cells treated with 50 μM nCTZ was increased 3.4 times compared to control (Fig 9A and 9B for control and 50 μM nCTZ, respectively). Moreover, 50 μM nCTZ also promoted necrosis because PI staining was positive after this treatment (Fig 9B). However, after treatment with 100 μM nCTZ, significant increases of both PI and annexin V staining were observed (Fig 9C).


Nanomicellar Formulation of Clotrimazole Improves Its Antitumor Action toward Human Breast Cancer Cells.

Marcondes MC, Fernandes AC, Itabaiana I, de Souza RO, Sola-Penna M, Zancan P - PLoS ONE (2015)

FACS analyses of MCF-7 cells treated with nanomicellar CTZ.The experimental procedures are described in Materials and Methods. Panel A: non-treated control cells. Panel B: MCF-7 cells treated with 50 μM nCTZ. Panel C: MCF-7 cells treated with 100 μM nCTZ. The percentage of cells in each quadrant is given.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476588&req=5

pone.0130555.g009: FACS analyses of MCF-7 cells treated with nanomicellar CTZ.The experimental procedures are described in Materials and Methods. Panel A: non-treated control cells. Panel B: MCF-7 cells treated with 50 μM nCTZ. Panel C: MCF-7 cells treated with 100 μM nCTZ. The percentage of cells in each quadrant is given.
Mentions: Membrane cell damage and nuclear condensation suggest that both necrosis and apoptosis are occurring as a result of nCTZ treatment. Therefore, we evaluated the PI and annexin V staining of MCF-7 cells treated for 24 hours with 50 μM or 100 μM nCTZ by FACS analysis. These experiments revealed that the annexin V staining of MCF-7 cells treated with 50 μM nCTZ was increased 3.4 times compared to control (Fig 9A and 9B for control and 50 μM nCTZ, respectively). Moreover, 50 μM nCTZ also promoted necrosis because PI staining was positive after this treatment (Fig 9B). However, after treatment with 100 μM nCTZ, significant increases of both PI and annexin V staining were observed (Fig 9C).

Bottom Line: We found that nCTZ was more efficient than sCTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes.This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism.Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Oncobiologia Molecular (LabOMol), Departamento de Biotecnologia Farmacêutica (BioTecFar), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.

ABSTRACT

Background: Although demonstrated as a selective anticancer drug, the clinical use of clotrimazole (CTZ) is limited due to its low solubility in hydrophilic fluids. Thus, we prepared a water-soluble nanomicellar formulation of CTZ (nCTZ) and tested on the human breast cancer cell line MCF-7 biology.

Methodology/principal findings: CTZ was nanoencapsulated in tween 80 micelles, which generated nanomicelles of, approximately, 17 nm of diameter. MCF-7 cells were treated with nCTZ and unencapsulated DMSO-solubilized drug (sCTZ) was used for comparison. After treatment, the cells were evaluated in terms of metabolism, proliferation, survival and structure. We found that nCTZ was more efficient than sCTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes. Moreover, this increased activity was also observed for lactate production, intracellular ATP content, ROS production and antioxidant potential. As a consequence, nCTZ-treated MCF-7 cells displayed alterations to the plasma membrane, mitochondria and the nucleus. Finally, nCTZ induced both apoptosis and necrosis in MCF-7 cells.

Conclusions/significance: MCF-7 cells are more sensible to nCTZ than to sCTZ. This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism. Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine.

No MeSH data available.


Related in: MedlinePlus