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

Marcondes, Mariah C.; Fernandes, Arlete; Itabaiana, Ivaldo; Souza, Rodrigo O. M. A. de; Sola‐Penna, Mauro; Zancan, Patrícia

doi:10.1371/journal.pone.0130555

Cited by 16 publications

(8 citation statements)

References 58 publications

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“…We were not able here to precise the ratio between the three PFK isoforms, but our data suggest that the total amount of the enzyme was decreased due to the lower total enzyme activity. The lack of responsiveness of the other markers is particularly surprising since PFK inhibition itself has been shown to decrease cancer cell viability and induction of apoptosis [Meira et al, ; Zancan et al, ; Spitz et al, ; Marcondes et al, ; Sola‐Penna et al, ; Coelho et al, ; Grechi et al, ; Furtado et al, ; Gomez et al, ; Marcondes et al, ], both effects not observed here. However, these works have not attributed the effects to any particular isoform of PFK.…”

Section: Discussionmentioning

confidence: 66%

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Phosphofructokinase‐P Modulates P44/42 MAPK Levels in HeLa Cells

Pires

Albanese

Schwab³

et al. 2017

J of Cellular Biochemistry

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It is known that interfering with glycolysis leads to profound modification of cancer cell proliferation. However, energy production is not the major reason for this correlation. Here, using HeLa cells as a model for cancer, we demonstrate that phosphofructokinase-P (PFK-P), which is overexpressed in diverse types of cancer including HeLa cells, modulates expression of P44/42 mitogen-activated protein kinase (MAPK). Silencing of PFK-P did not alter HeLa cell viability or energy production, including the glycolytic rate. On the other hand, silencing of PFK-P induced the downregulation of p44/42 MAPK, augmenting the sensitivity of HeLa cells to different drugs. Conversely, overexpression of PFK-P promotes the upregulation of p44/42 MAPK, making the cells more resistant to the drugs. These results indicate that overexpression of PFK-P by cancer cells is related to activation of survival pathways via upregulation of MAPK and suggest PFK-P as a promising target for cancer therapy. J. Cell. Biochem. 118: 1216-1226, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 66%

“…Glucose consumption, lactate production, ATP content and the activities of hexokinase, phosphofructokinase, pyruvate kinase, and glucose‐6‐phosphate dehydrogenase were evaluated as described previously [Marcondes et al, ].…”

Section: Methodsmentioning

confidence: 99%

Phosphofructokinase‐P Modulates P44/42 MAPK Levels in HeLa Cells

Pires

Albanese

Schwab³

et al. 2017

J of Cellular Biochemistry

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“…In breast cancer cells, CTZ reduces the activity of G6PDH (54), as well as interferes with the cell's glutathione levels, which favors the accumulation of ROS (58). These conditions may not occur in isolation since the HKII linked to mitochondrial VDAC participates in the production of intramitochondrial ROS, and its detachment from VDAC might increase oxidative stress (59,60).…”

Section: Discussionmentioning

confidence: 99%

Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells

et al. 2022

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Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation. In the present work, we employed a well-known erythroleukemia cell line, K562, and a multidrug resistant derivative cell, FEPS, to evaluate how hexokinase II, a key regulator for the rate-limiting step glycolysis, contributes to the establishment of the multidrug resistance phenotype. We found that multidrug resistant cells primarily resort to glycolysis to generate ATP. Clotrimazole reduced the expression of mitochondrial hexokinase II, which destabilized bioenergetic parameters such as reactive oxygen species production, ATP, and glutathione levels on multidrug resistant cells. This impaired the activity of ABCC1, leading to increased drug accumulation and cell death. In summary, we propose that decoupling of hexokinase II from the mitochondria emerges as a promising strategy to generate collateral sensitivity and aid in the management of chronic myeloid leukemia in chemotherapy-refractory patients.

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“…In this manner, CTZ inhibits the major enzymes involved in glycolysis, such as hexokinase, phosphofructokinase-1, and pyruvate kinase ( Furtado et al ., 2012 , 2015 ). This is the probable mechanism for CTZ-induced inhibition of proliferation of breast cancer cells, especially of the highly metastatic cells, MDA-MB-231 ( Furtado et al ., 2012 ; Marcondes et al ., 2015 ). However, the mechanism of action of CTZ has not been clearly explained.…”

Section: Discussionmentioning

confidence: 99%

Imidazole Antifungal Drugs Inhibit the Cell Proliferation and Invasion of Human Breast Cancer Cells

Bae

Park

Choi

et al. 2018

Biomol Ther (Seoul)

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Breast cancer is currently the most prevalent cancer in women, and its incidence increases every year. Azole antifungal drugs were recently found to have antitumor efficacy in several cancer types. They contain an imidazole (clotrimazole and ketoconazole) or a triazole (fluconazole and itraconazole) ring. Using human breast adenocarcinoma cells (MCF-7 and MDA-MB-231), we evaluated the effects of azole drugs on cell proliferation, apoptosis, cell cycle, migration, and invasion, and investigated the underlying mechanisms. Clotrimazole and ketoconazole inhibited the proliferation of both cell lines while fluconazole and itraconazole did not. In addition, clotrimazole and ketoconazole inhibited the motility of MDA-MB-231 cells and induced G1-phase arrest in MCF-7 and MDA-MB-231 cells, as determined by cell cycle analysis and immunoblot data. Moreover, Transwell invasion and gelatin zymography assays revealed that clotrimazole and ketoconazole suppressed invasiveness through the inhibition of matrix metalloproteinase 9 in MDA-MB-231 cells, although no significant changes in invasiveness were observed in MCF-7 cells. There were no significant changes in any of the observed parameters with fluconazole or itraconazole treatment in either breast cancer cell line. Taken together, imidazole antifungal drugs showed strong antitumor activity in breast cancer cells through induction of apoptosis and G1 arrest in both MCF-7 and MDA-MB-231 cells and suppression of invasiveness via matrix metalloproteinase 9 inhibition in MDA-MB-231 cells. Imidazole drugs have well-established pharmacokinetic profiles and known toxicity, which can make these generic drugs strong candidates for repositioning as antitumor therapies.

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

Cited by 16 publications

References 58 publications

Phosphofructokinase‐P Modulates P44/42 MAPK Levels in HeLa Cells

Phosphofructokinase‐P Modulates P44/42 MAPK Levels in HeLa Cells

Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells

Imidazole Antifungal Drugs Inhibit the Cell Proliferation and Invasion of Human Breast Cancer Cells

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