Clinical significance of apoptotic index in non-small cell lung cancer: correlation with p53, mdm2, pRb and p21WAF1/CIP1 protein expression

Dworakowska, Dorota; Jassem, Ewa; Jassem, Jacek; Karmolinski, Andrzej; Dworakowski, Rafał; Wirth, Thomas; Gruchała, Marcin; Rynkiewicz, Andrzej; Skokowski, Jan; Yla-Herttuala, S.; Jaskiewicz, K; Czestochowska, E

doi:10.1007/s00432-005-0010-7

Cited by 12 publications

(13 citation statements)

References 20 publications

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“…In this study we attempted to verify our previous findings that elevated AI negatively influences survival in NSCLC patients by looking at a larger group of parameters in an extended population sample [11]. The previous study was small (50 NSCLC patients), and we noted then that the results should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 78%

“…This group included 50 NSCLC patients from pilot study [11]. Written informed consent was obtained from all patients before inclusion in the study.…”

Section: Patientsmentioning

confidence: 99%

“…TUNEL assay and immunohistochemistry (p53, pRb, mdm2, p21 WAF1/CIP1 , cyclin D1, PCNA) Apoptosis of tumor cells was detected with the use of ApopTag ® Plus Peroxidase In Situ Apoptosis Detection Kit (S7101-kit, Intergen Company, Oxford, UK) based on TdT-mediated deoxyuridine triphosphate-biotin/digoxygenin nick end-labeling (TUNEL technique). The TUNEL assay was performed directly according to the manufacturers' instructions, as previously described [11]. Apoptotic cells were determined with observation of TUNEL-stained sections and serial HE-stained sections.…”

Section: Patientsmentioning

confidence: 99%

“…In our previous pilot study of a small series of 50 surgically treated NSCLC patients, we assessed the prognostic value of the apoptotic index (AI), analysed in conjunction with p53, pRb, mdm2 and p21 WAF1/CIP1 expression. We found that higher AI negatively influenced patient survival and negatively correlated with mdm2 protein expression [11].…”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Prognostic value of the apoptotic index analysed jointly with selected cell cycle regulators and proliferation markers in non-small cell lung cancer

Dworakowska

Jassem

et al. 2009

Lung Cancer

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Section: Discussionmentioning

confidence: 78%

“…This group included 50 NSCLC patients from pilot study [11]. Written informed consent was obtained from all patients before inclusion in the study.…”

Section: Patientsmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Prognostic value of the apoptotic index analysed jointly with selected cell cycle regulators and proliferation markers in non-small cell lung cancer

Dworakowska

Jassem

et al. 2009

Lung Cancer

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“…Techniques for analysis of NY-ESO-1, MAGE-3, p16, acetylated histone H4, and p21 expression in biopsy tissues have been previously described (18,24,25). For analysis of Ki-67, phospho-ERK, and cleaved caspase-3, tissue sections were incubated in citrate buffer (pH 6.0; DAKO) for 1 h in a water bath at 95jC for antigen retrieval.…”

Section: Romidepsin In Lung Cancer Patientsmentioning

confidence: 99%

Clinical and Molecular Responses in Lung Cancer Patients Receiving Romidepsin

Schrump¹,

Fischette²,

Nguyen³

et al. 2008

Clinical Cancer Research

114

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Purpose: Our preclinical experiments indicated that Romidepsin (Depsipeptide FK228; DP) mediates growth arrest and apoptosis in cultured lung cancer cells. A phase II trial was done to examine clinical and molecular responses mediated by this histone deacetylase inhibitor in lung cancer patients. Experimental Design: Nineteen patients with neoplasms refractory to standard therapy received 4-h DP infusions (17.8 mg/m 2 ) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of two identical 21-day cycles. Plasma DP levels were evaluated by liquid chromatography^mass spectrometry techniques. A variety of molecular end points were assessed in tumor biopsies via immunohistochemistry techniques. Long oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after DP exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections. Results: Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in one individual. No significant cardiac toxicities were observed. Maximum steady-state plasma DP concentrations ranged from 384 to 1,114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in nine patients. DP enhanced acetylation of histone H4, increased p21expression in lung cancer cells, and seemed to shift global gene expression profiles in these cells toward those detected in normal bronchial epithelia. Conclusion: Although exhibiting minimal clinical efficacy at this dose and schedule, DP mediates biological effects that may warrant further evaluation of this histone deacetylase inhibitor in combination with novel-targeted agents in lung cancer patients.Dynamic patterns of gene expression during embryonic development and cellular homeostasis, as well as stable repression of gene expression associated with X chromosome inactivation and imprinting, are mediated via DNA methylation in conjunction with acetylation, methylation, and phosphorylation of core histone proteins (H2a, H2b, H3, and H4; refs. 1, 2). Perturbation of these tightly linked epigenetic processes during multistep pulmonary carcinogenesis results in global DNA demethylation, derepression of endogenous retroviruses and germ cell -restricted genes, such as BORIS, NY-ESO-1, and MAGE-3, and paradoxical silencing of a variety of tumor suppressor genes, including p16, p14/ARF, TFPI-2, and RASSF1A (3 -5).Whereas considerable literature pertains to mechanisms contributing to aberrant DNA methylation in cancer cells (6), less information is available regarding specific histone modifications that arise during malignant transformation. However, recent studies indicate that unique changes in the histone code occur early during multistep carcinogenesis and contribute significantly to altered chromatin structure and gene expression in cancer cells (7). For example, leukemia and breast cancer cells exhibit loss of monoacetylati...

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Genome‐wide CRISPR/Cas9 screening for therapeutic targets in NSCLC carrying wild‐type TP53 and receptor tyrosine kinase genes

Wang

Zhu

et al. 2022

Clinical & Translational Med

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Background Targeted drugs have greatly improved the therapeutic outcome of non‐small cell lung cancer (NSCLC) patients compared with conventional chemotherapy, whereas about one‐third of patients are so far not suitable for targeted therapy due to lack of known driver oncogenes such as a mutated receptor tyrosine kinase (RTK) genes. In this study, we aimed to identify therapeutic targets for this subgroup of NSCLC patients. Methods We performed genome‐wide CRISPR/Cas9 screens in two NSCLC cell lines carrying wild‐type TP53 and receptor tyrosine kinase (wtTP53‐RTK) genes using a GeCKO v2.0 lentiviral library (containing 123411 sgRNAs and targeting 19050 genes). MAGeCKFlute was used to analyse and identify candidate genes. Genetic perturbation and pharmacological inhibition were used to validate the result in vitro and in vivo. Results The Genome‐wide CRISPR/Cas9 screening identified MDM2 as a potential therapeutic target for wtTP53‐RTK NSCLC. Genetic and pharmacological inhibition of MDM2 reduced cell proliferation and impaired tumour growth in the xenograft model, thus confirming the finding of the CRISPR/Cas9 screening. Moreover, treatment by a selective MDM2 inhibitor RG7388 triggered both cell cycle arrest and apoptosis in several NSCLC cell lines. Additionally, RG7388 and pemetrexed synergistically blocked the cell proliferation and growth of wtTP53‐RTK tumours but had limited effects for other genotypes. Conclusions We identified MDM2 as an essential gene and a potential therapeutic target in wtTP53‐RTK NSCLC via a genome‐wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.

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Clinical significance of apoptotic index in non-small cell lung cancer: correlation with p53, mdm2, pRb and p21WAF1/CIP1 protein expression

Abstract: These results suggest that AI correlates with mdm2 protein expression and influences survival in NSCLC.

Cited by 12 publications

References 20 publications

Prognostic value of the apoptotic index analysed jointly with selected cell cycle regulators and proliferation markers in non-small cell lung cancer

Prognostic value of the apoptotic index analysed jointly with selected cell cycle regulators and proliferation markers in non-small cell lung cancer

Clinical and Molecular Responses in Lung Cancer Patients Receiving Romidepsin

Genome‐wide CRISPR/Cas9 screening for therapeutic targets in NSCLC carrying wild‐type TP53 and receptor tyrosine kinase genes

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