Targeting cell cycle regulation in cancer therapy

Díaz-Moralli, Santiago; Tarrado‐Castellarnau, Míriam; Miranda, Aníbal; Cascante, Marta

doi:10.1016/j.pharmthera.2013.01.011

Cited by 310 publications

(231 citation statements)

References 243 publications

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“…The cell cycle machinery, which functions as an integration point for information transduced via upstream signaling networks, is a target for potential diagnostic and therapeutic interventions (13)(14)(15). Apoptosis is a physiological cell death process that has key functions in normal development, as well as in the pathophysiology of various diseases (16,17).…”

Section: Dysregulation Of the Pi3k/akt Signaling Pathway Affects Cellmentioning

confidence: 99%

“…However, the molecular mechanisms underlying the modulation of these stem-like cell populations in NPC have remained elusive. Cellular proliferation is a critical process underlying the growth, development and regeneration of eukaryotic organisms, and appropriate control of the cell cycle is required for the proliferation of normal cells (13,14). Deregulation of the cell cycle is responsible for the aberrant cell proliferation characteristic of cancer, and the loss of cell cycle checkpoint control, …”

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confidence: 99%

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Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma

et al. 2015

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Abstract.Increasing evidence has suggested that certain types of cancer possess their own stem-like cells, and that one subset of these cells, termed the side population (SP), may have an important role in tumorigenesis and cancer therapy. However, the molecular mechanisms underlying the modulation of SP cells in nasopharyngeal carcinoma (NPC) have remained elusive. In the present study, it was hypothesized that dysregulation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signaling pathway may influence SP and non-SP (NSP) phenotype. SP cells from the HK-1 NPC cell line were identified, and cancer stem cell markers were found to be highly expressed in SP cells compared with that of NSP cells. Freshly sorted SP cells demonstrated a significant increase in the proportion of cells in G0/G1 phase, while the majority of NSP cells were in the proliferative phase. Following 48 h of culture subsequent to cell sorting, the differences in cell cycle distribution between the SP and NSP cells converged. In addition, the apoptotic ratio of NSP cells was higher than that of SP cells at 24 h following sorting, but had no significant differences 48 h following sorting. To elucidate the potential mechanism mediating the cell cycle and apoptosis in SP cells, the expression levels of key molecules in the PI3K/Akt signaling pathway were evaluated. PI3K and Akt were upregulated, while 14-3-3σ protein was downregulated in SP cells when freshly sorted (0 h). However, there was no significant difference in the expression of these molecules between SP and NSP cells following 48 h of culture. These results suggested that dysregulation of the PI3K/Akt signaling pathway may be associated with the cell cycle and apoptosis of SP cells in NPC. However, further investigation is required to elucidate the detailed mechanisms underlying these effects. IntroductionIncreasing evidence has suggested that specific types of cancer may contain their own stem-like cells, known as cancer stem cells (CSCs), which have key roles in the initiation, maintenance and recurrence of tumors (1-3). In particular, attention has been paid to a subset of CSCs, termed the side population (SP), which was identified by flow cytometry. These SP cells are able to exclude the DNA binding dye, Hoechst 33342, and are highly enriched for stem cells in numerous types of tissue (4-6). SP cells have been isolated from multiple solid tumors, and studies have suggested that they may have significant roles in tumorigenesis and cancer therapy. A SP of cells in nasopharyngeal carcinoma (NPC) were found to exhibit characteristics of stem-like cancer cells (7-12). However, the molecular mechanisms underlying the modulation of these stem-like cell populations in NPC have remained elusive. Cellular proliferation is a critical process underlying the growth, development and regeneration of eukaryotic organisms, and appropriate control of the cell cycle is required for the proliferation of normal cells (13,14). Deregulation of the cell cycle is responsible for the aberrant...

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Section: Dysregulation Of the Pi3k/akt Signaling Pathway Affects Cellmentioning

confidence: 99%

mentioning

confidence: 99%

Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma

et al. 2015

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“…Thus, cell cycle arrest is approved one of the target mechanisms for cancer therapy. 34 Nguyen et al showed that bilberry extract inhibits human breast cancer cell proliferation in a dosedependent manner in concert with induction of apoptotic cell death but no effect is observed on cell cycle in lowest concentrations. Hovewer, higher extract concentrations which cause an arrest of cells at the G 2 /M phase of the cell cycle and modify microtubule organization, 35 while Naowaratwattana et al reported that M. alba leaf extract inhibits the proliferation of HepG2 cells in a dose-dependent manner by inducing cell cycle arrest at G 2 /M phase, caspase activity and inhibiting topoisomerase IIα activity.…”

Section: Discussionmentioning

confidence: 99%

Morus rubra Extract Induces G1 Cell Cycle Arrest and Apoptosis in Human Lung and Prostate Cancer Cells

Turan¹,

Demir²,

Kilinç³

et al. 2017

IJPER

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Objective: Cancer is one of the most deadly types of disease and evasion from apoptosis and unstoppable cell proliferation are accepted as its distinctive features. Many studies have evaluated the cytotoxic effect of different Morus species but, there is no study about cytotoxic effect of Morus rubra. In this study we aimed to evaluate phenolic composition, antioxidant properties and cytotoxic effect of acidified dimethyl sulfoxide extract of M. rubra (AMRE). Method: Antioxidant properties, phenolic composition and cytotoxic effect of AMRE were determined using spectrophotometric methods, HPLC, and MTT assay, respectively. Then, mechanisms of cytotoxic effect of AMRE on human prostate (PC-3) and lung (A549) cancer cells were examined in regard to cell cycle, apoptosis and mitochondrial membrane potential using flow cytometric methods. Results: Total phenolic content and reducing power values were 11.9 mg gallic acid equivalents and 42.9 mg trolox equivalents per g sample, respectively. Ascorbic and gallic acid were detected in AMRE as major antioxidant compounds. We determined that AMRE increased cell cycle arrest at G 1 phase and exhibited apoptotic features via decreasing mitochondrial membrane potential in both prostate and lung cancer cells. Conclusion: These findings demonstrate that M. rubra extract can affect the behavior of human prostate and lung cancer cells in vitro conditions, and this effect now needs to be investigated in vivo.

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“…Cell cycle progression is orchestrated by a complex network of interactions between proteins, including cyclins, CDKs, E3 ubiquitin ligase complexes, CDK activating kinase, CDC25 phosphatases and CDK inhibitors (19). To explore the mechanisms by which AEXHP induces cell cycle arrest in Hs578T cells at S phase, western blot analysis was used to assess the modulation of the expression of cell cycle regulatory proteins by AEXHP.…”

Section: Discussionmentioning

confidence: 99%

Multiple effects of Xihuang pill aqueous extract on the Hs578T triple-negative breast cancer cell line

et al. 2016

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Abstract. The management of triple-negative breast cancer (TNBC) is challenging due to the aggressive behavior, lack of therapeutic options and relatively poor prognosis. Xihuang pill (XHP) is a well-known Traditional Chinese Medicine with anticancer activity. The aim of the present study was to investigate whether the aqueous extract of XHP (AEXHP) has anti-proliferative activity against the Hs578T TNBC cell line, and to elucidate its molecular mechanisms of action. First, an MTT assay was used to evaluate the anti-proliferative activity of AEXHP on the Hs578T cell line; furthermore, the cell cycle distribution, mitochondrial membrane potential and apoptotic rate were determined by flow cytometry, and western blot analysis was used to assess the expression of apoptosis and cell cycle regulatory proteins to investigate the mechanisms of action. The results revealed that the cell viability was significantly inhibited by AEXHP in a dose-and time-dependent manner. Apoptosis and mitochondrial membrane potential loss were detected, and after treatment with 4, 8 and 12 mg/ml AEXHP for 24 h, cleaved caspase-3 was 1.70-, 1.81-and 1.84-fold of that of the control, while procaspase-3, procaspase-8, cleaved caspase-8, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and the Bcl-2/Bax ratio were not significantly affected. Cell cycle analysis revealed that treatment with AEXHP led to S-phase arrest of Hs578T cells. Furthermore, AEXHP treatment resulted in decreased expression of cyclin A and cyclin dependent kinase 2 (CDK2), and increased expression of cyclin E and p21 Cip1, as compared to the control group. In conclusion, the viability of Hs578T cells was significantly inhibited by AEXHP in a dose-and time-dependent manner, the likely mechanisms of which being induction of apoptosis, probably via the intrinsic, Bcl-2-independent pathway, and cell cycle arrest in S phase due to decreased expression of cyclin A and CDK2, and increased expression of cyclin E and p21

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Targeting cell cycle regulation in cancer therapy

Cited by 310 publications

References 243 publications

Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma

Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma

Morus rubra Extract Induces G1 Cell Cycle Arrest and Apoptosis in Human Lung and Prostate Cancer Cells

Multiple effects of Xihuang pill aqueous extract on the Hs578T triple-negative breast cancer cell line

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