Identification of pharmacodynamic biomarkers and common molecular mechanisms of response to genotoxic agents in cancer cell lines

Min, Dong-Joon; Zhao, Yingdong; Monks, Anne; Palmisano, Alida; Hose, Curtis; Teicher, Beverly A.; Doroshow, James H.; Simon, Richard

doi:10.1007/s00280-019-03898-z

Cited by 7 publications

(2 citation statements)

References 64 publications

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“…Thus, complex 7 can induce a p21-dependent cell cycle arrest both in cisplatin-sensitive and resistant cells at concentrations ≤1 µM. In addition, complex 7 promotes an upregulation of the apoptosis inducer CHOP that is overexpressed by various genotoxic agents in sensitive cells [ 99 ]. The stronger upregulation in SKOV3 compared to A2780 cells resembles the higher levels of apoptosis and cell death in this cell line ( Figure 2 and Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization and Biological Investigation of the Platinum(IV) Tolfenamato Prodrug–Resolving Cisplatin-Resistance in Ovarian Carcinoma Cell Lines

Barth

Häfner

Runnebaum

et al. 2023

IJMS

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The research on the anticancer potential of platinum(IV) complexes represents one strategy to circumvent the deficits of approved platinum(II) drugs. Regarding the role of inflammation during carcinogenesis, the effects of non-steroidal anti-inflammatory drug (NSAID) ligands on the cytotoxicity of platinum(IV) complexes is of special interest. The synthesis of cisplatin- and oxaliplatin-based platinum(IV) complexes with four different NSAID ligands is presented in this work. Nine platinum(IV) complexes were synthesized and characterized by use of nuclear magnetic resonance (NMR) spectroscopy (1H, 13C, 195Pt, 19F), high-resolution mass spectrometry, and elemental analysis. The cytotoxic activity of eight compounds was evaluated for two isogenic pairs of cisplatin-sensitive and -resistant ovarian carcinoma cell lines. Platinum(IV) fenamato complexes with a cisplatin core showed especially high in vitro cytotoxicity against the tested cell lines. The most promising complex, 7, was further analyzed for its stability in different buffer solutions and behavior in cell cycle and cell death experiments. Compound 7 induces a strong cytostatic effect and cell line-dependent early apoptotic or late necrotic cell death processes. Gene expression analysis suggests that compound 7 acts through a stress-response pathway integrating p21, CHOP, and ATF3.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization and Biological Investigation of the Platinum(IV) Tolfenamato Prodrug–Resolving Cisplatin-Resistance in Ovarian Carcinoma Cell Lines

Barth

Häfner

Runnebaum

et al. 2023

IJMS

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“…In contrast, Regorafenib-treated U87MG cells show prominent pathways for the "Response of EIF2AK1 (HRI) to heme deficiency", "Netrin-1 signaling", "Serine biosynthesis", and "Transcriptional activation of mitochondrial biogenesis" pathways (Table S2). The "Response of EIF2AK1 (HRI) to heme deficiency" pathway signature contains the component genes DDIT3, TRIB3, ATF3, and ASNS, a grouping associated with endoplasmic reticulum (ER) stress, and characteristic of genotoxic agents [51]. DDIT3 is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors.…”

Section: Pathway Enrichment Analysis For the Upregulated U87mg Gene Setsmentioning

confidence: 99%

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

Шаповалов¹,

Kopanitsa²,

Pruteanu³

et al. 2021

Cancers

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We have used three established human glioblastoma (GBM) cell lines—U87MG, A172, and T98G—as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come.

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Integrated biomarker responses: Unveiling insights through serum biochemistry, oxidative stress, genotoxicity and histopathology

Shukla,

Prasad,

Singh

2024

Biomarkers in Environmental and Human Health Biomonitoring

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Identification of pharmacodynamic biomarkers and common molecular mechanisms of response to genotoxic agents in cancer cell lines

Cited by 7 publications

References 64 publications

Synthesis, Characterization and Biological Investigation of the Platinum(IV) Tolfenamato Prodrug–Resolving Cisplatin-Resistance in Ovarian Carcinoma Cell Lines

Synthesis, Characterization and Biological Investigation of the Platinum(IV) Tolfenamato Prodrug–Resolving Cisplatin-Resistance in Ovarian Carcinoma Cell Lines

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

Integrated biomarker responses: Unveiling insights through serum biochemistry, oxidative stress, genotoxicity and histopathology

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