Cell cycle G2/M arrest and activation of cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis

Shu, Chih Hung; Yang, Wei‐Pang; Shih, Yu‐Lueng; Kuo, Min-Liang; Huang, Tze-Sing

doi:10.1023/a:1026422111457

Cited by 57 publications

(45 citation statements)

References 40 publications

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“…on May 10, 2018. by guest www.bloodjournal.org From increase in apoptotic cells at the 48-hour time point ( Figure 5G; one-way repeated measures analysis of variance, n ϭ 3, P Ͻ .01; Tukey posthoc analysis: control vs siRNA 1, P Ͻ .05; control vs siRNA 2, P Ͻ .001). Consistent with the increased annexin V staining, an increase in the size of the sub-G 1 population, representing apoptotic cells, 43 was seen at the 48-hour time point (supplemental Figure 4).…”

Section: Id1 Promotes Expansion/survival Of Erythroid Cells 1825supporting

confidence: 62%

ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling

Wood

Chen

Donaldson

et al. 2009

Blood

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IntroductionThroughout mammalian life there is a continual turnover of the cellular components of the blood, ultimately driven by a small population of hematopoietic stem cells located within the bone marrow. 1 Erythropoiesis is first detected within the blood islands of the murine yolk sac at embryonic days 7 to 7.5. 2 This first wave of primitive erythropoiesis is transient and erythropoietin independent 3 and is replaced by a second wave of definitive erythropoiesis that takes place first within the fetal liver and later in the bone marrow and spleen. 1 Unlike primitive erythropoiesis, definitive erythropoiesis is dependent on erythropoietin, 4 although terminal differentiation and enucleation of late basophilic erythroblasts is erythropoietin independent. 5 Erythropoietin levels regulate red cell production by regulating the rate of apoptosis within developing erythroblasts. 6 When circulating erythropoietin levels are low, a high proportion of erythroblasts undergoes apoptosis; increasing levels of erythropoietin rescue an increasing proportion of the total erythroblasts from apoptosis, thereby increasing the rate of production of mature red cells. 7 Signaling by the erythropoietin receptor is critically dependent on the cytoplasmic tyrosine kinase JAK2 8 and leads, among other things, to the phosphorylation and nuclear translocation of the transcription factor STAT5. 9 JAK2-STAT5 signaling has taken on a new clinical significance since the discovery of an acquired mutation in the JAK2 gene in patients with myeloproliferative disorders (MPDs). [10][11][12] The JAK2V617F mutation is found in more than 95% of patients with polycythemia vera (PV) and in approximately 50% of those with essential thrombocythemia (ET) and idiopathic myelofibrosis. [13][14][15][16] Several observations suggest that the JAK2V617F mutation produces an increased erythroid drive and that the level of the resulting signaling influences the degree to which erythropoiesis is stimulated. (1) Retroviral and transgenic mouse models demonstrate that mutant JAK2 produces an erythrocytosis in vivo and are consistent with the concept that an increased copy number of mutant JAK2 alleles results in a more erythroid phenotype. [17][18][19][20][21][22] (2) JAK2V617F-positive patients with ET and idiopathic myelofibrosis have increased blood hemoglobin levels, increased bone marrow erythropoiesis, and/or reduced serum erythropoietin levels compared with those negative for the JAK2V617F mutation. 23,24 (3) Subclones homozygous for the V617F mutation are common in patients with overt PV but not in those with JAK2V617F positive ET. 25 (4) Patients with no V617F mutation but who have JAK2 exon 12 mutations define a subtype of PV characterized by an isolated and more marked increase in erythropoiesis, which is associated with increased levels of activation of downstream signaling pathways compared with patients with the V617F mutation. 26 Both JAK2V617F and constitutively active forms of STAT5 recapitulate many of the features of PV both in vitro 14,27,2...

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Section: Id1 Promotes Expansion/survival Of Erythroid Cells 1825supporting

confidence: 62%

ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling

Wood

Chen

Donaldson

et al. 2009

Blood

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“…However, when paclitaxel was given 6, 12, or 24 hours before rapamycin administration, an increase in cells in G 2 -M phase was observed, similar to that observed on single-agent paclitaxel therapy. G 2 -M arrest has been proposed to be a prerequisite step for apoptosis induced by paclitaxel (26); therefore, our results suggest that delayed rapamycin treatment may enhance paclitaxelinduced apoptosis by allowing cells to progress to G 2 -M arrest.…”

Section: Resultsmentioning

confidence: 53%

Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells

Mondesire

Jian

Zhang

et al. 2004

Clinical Cancer Research

294

219

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Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first-and second-line agents against breast cancer.Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model.Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel-and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors.Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.

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“…Paclitaxel treatment arrests the cell cycle at G 2 -M phase by preventing the depolymerization of microtubules, resulting in apoptotic cell death (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

Cerquetti

Sampaoli

Salvo

et al. 2015

International Journal of Oncology

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Abstract. C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G 2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by procaspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines. IntroductionAdrenocortical carcinoma (ACC) is a rare endocrine neoplasia with a variable prognosis, depending on tumor stage and time of diagnosis, but it is generally fatal, with an overall survival of 5 years from detection (1-3). Metastasis associated with ACCs can range from 30 to 85% (4).More recently, elevated or deregulated expression of the c-Myc protein has been detected in a wide range of human cancers, and is often associated with aggressive and poorly differentiated tumors. C-MYC belongs to the class of immediate early genes which are induced in response to a number of mitogenic signals. It encodes a nuclear transcription factor leading to activation or repression of target genes, thus affecting several biological processes, such as cellular growth, differentiation, cell cycle and apoptosis (5,6). Surprisingly, gene expression profile studies have demonstrated an underexpression of C-MYC in ACC compared to adrenocortical adenoma (7-10).The treatment with DNA-damaging agents can sensitize cells to apoptosis when c-Myc is overexpressed (11), but its role in cellular susceptibility to anticancer drugs is controversial. It has been reported that the overexpression of c-Myc not only enhances tumor cell sensitivity (12) but also induces resistance to antineoplastic agents (13).It has been widely demonstrated that cells expressing high c-Myc levels show an apoptosis-prone phenotype in response to different stimuli, affecting cell c...

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Cell cycle G2/M arrest and activation of cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis

Cited by 57 publications

References 40 publications

ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling

ID1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signaling

Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines

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