RB Activity Alters Checkpoint Response and Chemosensitivity in Lung Cancer Lines

Reed, Michael F.; Zagórski, W; Knudsen, Erik S.

doi:10.1016/j.jss.2007.03.038

Cited by 9 publications

(10 citation statements)

References 35 publications

(43 reference statements)

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“…The retinoblastoma tumor suppressor (RB) is a key regulator of cell cycle progression and is functionally inactivated in the majority of NSCLC tumors608. Hypophosphorylated RB blocks cell cycle progression, and phosphorylation of RB (to form pRB) inactivates RB, permitting progression through the cell cycle.…”

Section: 0 Cell Cyclingmentioning

confidence: 99%

“…Hypophosphorylated RB blocks cell cycle progression, and phosphorylation of RB (to form pRB) inactivates RB, permitting progression through the cell cycle. Transfection of RB into RB-deficient NSCLC cells enhanced the G1 checkpoint response to chemotherapy608. Transfection of RB into RB-deficient NSCLC608 or SCLC609 cells also significantly increased resistance608 or resulted in a trend towards increased resistance609 to cisplatin608, 609, etoposide608, 609, doxorubicin609 and 5-fluorouracil608, while dexamethasone-induced dephosphorylation of pRB in NSCLC cells was associated with antagonism of paclitaxel-induced cytotoxicity574.…”

Section: 0 Cell Cyclingmentioning

confidence: 99%

“…Transfection of RB into RB-deficient NSCLC cells enhanced the G1 checkpoint response to chemotherapy608. Transfection of RB into RB-deficient NSCLC608 or SCLC609 cells also significantly increased resistance608 or resulted in a trend towards increased resistance609 to cisplatin608, 609, etoposide608, 609, doxorubicin609 and 5-fluorouracil608, while dexamethasone-induced dephosphorylation of pRB in NSCLC cells was associated with antagonism of paclitaxel-induced cytotoxicity574. On the other hand, one study found that expression of RB protein in cell lines derived from biopsies of patients with NSCLC or SCLC did not correlate with in vitro chemotherapy resistance, nor with response to chemotherapy or survival of the patients from whom the cells were derived 609.…”

Section: 0 Cell Cyclingmentioning

confidence: 99%

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Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Stewart

2010

Critical Reviews in Oncology/Hematology

161

157

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While chemotherapy provides useful palliation, advanced lung cancer remains incurable since those tumors that are initially sensitive to therapy rapidly develop acquired resistance. Resistance may arise from impaired drug delivery, extracellular factors, decreased drug uptake into tumor cells, increased drug efflux, drug inactivation by detoxifying factors, decreased drug activation or binding to target, altered target, increased damage repair, tolerance of damage, decreased proapoptotic factors, increased antiapoptotic factors, or altered cell cycling or transcription factors. Factors for which there is now substantial clinical evidence of a link to small cell lung cancer (SCLC) resistance to chemotherapy include MRP (for platinum-based combination chemotherapy) and MDR1/P-gp (for non-platinum agents). SPECT MIBI and Tc-TF scanning appears to predict chemotherapy benefit in SCLC. In non-small cell lung cancer (NSCLC), the strongest clinical evidence is for taxane resistance with elevated expression or mutation of class III β-tubulin (and possibly α tubulin), platinum resistance and expression of ERCC1 or BCRP, gemcitabine resistance and RRM1 expression, and resistance to several agents and COX-2 expression (although COX-2 inhibitors have had minimal impact on drug efficacy clinically). Tumors expressing high BRCA1 may have increased resistance to platinums but increased sensitivity to taxanes. Limited early clinical data suggest that chemotherapy resistance in NSCLC may also be increased with decreased expression of cyclin B1 or of Eg5, or with increased expression of ICAM, matrilysin, osteopontin, DDH, survivin, PCDGF, caveolin-1, p21WAF1/CIP1, or 14-3-3sigma, and that IGF-1R inhibitors may increase efficacy of chemotherapy, particularly in squamous cell carcinomas. Equivocal data (with some positive studies but other negative studies) suggest that NSCLC tumors with some EGFR mutations may have increased sensitivity to chemotherapy, while K-ras mutations and expression of GST-pi, RB or p27kip1 may possibly confer resistance. While limited clinical data suggest that p53 mutations are associated with resistance to platinum-based therapies in NSCLC, data on p53 IHC positivity are equivocal. To date, resistance-modulating strategies have generally not proven clinically useful in lung cancer, although small randomized trials suggest a modest benefit of verapamil and related agents in NSCLC.

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Section: 0 Cell Cyclingmentioning

confidence: 99%

Section: 0 Cell Cyclingmentioning

confidence: 99%

Section: 0 Cell Cyclingmentioning

confidence: 99%

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Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Stewart

2010

Critical Reviews in Oncology/Hematology

161

157

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“…E2F1-induced apoptosis was previously demonstrated to correlate well with p53 stabilization in response to DNA damage, whereas in the absence of an active p53 protein, one or more E2F1 pro-apoptotic transcriptional targets, such as p73, Bim,were shown to be notably upregulated (Putzer 2007;Real et al 2006). On the other hand, p53-null cells have been denoted to be signiWcantly protected from apoptosis by Rb protein, in an E2F1-dependent manner (Angus et al 2002;Reed et al 2007). …”

Section: Fig 10mentioning

confidence: 99%

Thymidylate synthase inhibition induces p53-dependent and p53-independent apoptotic responses in human urinary bladder cancer cells

Stravopodis

Karkoulis

Konstantakou

et al. 2010

J Cancer Res Clin Oncol

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We have shown that in the wild-type p53 context of RT4 cells, 5-FU-triggered apoptosis was prominently efficient and mainly regulated by p53-dependent mechanisms, whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis, basically ascribed to E2F-independent, and still unidentified, pathways. Nevertheless, the differential vulnerability of RT4 and T24 cells to 5-FU administration could also be associated with cell-type-specific transcriptional expression patterns of certain genes critically involved in 5-FU metabolism.

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“…In our study, the highest resistance was observed for the anti-metabolite 5-FU, which is an S-phase dependent cytostatic. Its cytotoxic efficacy declined in Rb-knockdown clones by 10%–40% as compared to the nonsense control, irrespective of the Rb-knockdown extent (IC 50 = 41 µM), which could be explained by the slower growth of the modulated cell populations (data not shown) and by presumably increased levels of thymidilate synthase (TS), the cellular target of 5-FU, as described for cells without Rb [41]. A study performed on adult somatic cells revealed that following spontaneous immortalization and loss of functional p53, 5-FU failed to induce cell cycle arrest despite the presence of Rb [42].…”

Section: Resultsmentioning

confidence: 84%

Reduced Expression of the Retinoblastoma Protein Shows That the Related Signaling Pathway Is Essential for Mediating the Antineoplastic Activity of Erufosine

et al. 2014

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Erufosine is a new antineoplastic agent of the group of alkylphosphocholines, which interferes with signal transduction and induces apoptosis in various leukemic and tumor cell lines. The present study was designed to examine for the first time the mechanism of resistance to erufosine in malignant cells with permanently reduced expression of the retinoblastoma (Rb) protein. Bearing in mind the high number of malignancies with reduced level of this tumor-suppressor, this investigation was deemed important for using erufosine, alone or in combination, in patients with compromised RB1 gene expression. For this purpose, clones of the leukemic T-cell line SKW-3 were used, which had been engineered to constantly express differently low Rb levels. The alkylphosphocholine induced apoptosis, stimulated the expression of the cyclin dependent kinase inhibitor p27Kip1 and inhibited the synthesis of cyclin D3, thereby causing a G2 phase cell cycle arrest and death of cells with wild type Rb expression. In contrast, Rb-deficiency impeded the changes induced by eru-fosine in the expression of these proteins and abrogated the induction of G2 arrest, which was correlated with reduced antiproliferative and anticlonogenic activities of the compound. In conclusion, analysis of our results showed for the first time that the Rb signaling pathway is essential for mediating the antineoplastic activity of erufosine and its efficacy in patients with malignant diseases may be predicted by determining the Rb status.

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RB Activity Alters Checkpoint Response and Chemosensitivity in Lung Cancer Lines

Cited by 9 publications

References 35 publications

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Thymidylate synthase inhibition induces p53-dependent and p53-independent apoptotic responses in human urinary bladder cancer cells

Reduced Expression of the Retinoblastoma Protein Shows That the Related Signaling Pathway Is Essential for Mediating the Antineoplastic Activity of Erufosine

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