The novel atypical retinoid ST1926 is active in ATRA resistant neuroblastoma cells acting by a different mechanism

Francesco, Angela Maria Di; Meco, Daniela; Torella, Anna Rita; Barone, Giuseppe; D'Incalci, M.; Pisano, Claudio; Carminati, Paolo; Riccardi, Riccardo

doi:10.1016/j.bcp.2006.10.033

Cited by 30 publications

(40 citation statements)

References 25 publications

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“…The balance between pro-apoptotic and anti-apoptotic factors regulates the commitment of cells to death. The pro-apoptotic and the tumor suppressor molecule p53 is wild-type in neuroblastoma SK-N-DZ [26] and SH-SY5Y [27] cell lines but it is functionally inactive due to cytoplasmic sequestration [28]. We showed that upregulation of p53 and also the p53-targeted gene product p21 (cell cycle arresting protein) by the combination therapy (SF + GST) induced cell cycle arrest and apoptosis.…”

Section: Discussionmentioning

confidence: 94%

Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification

et al. 2009

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Neuroblastoma is an extracranial, solid, and heterogeneous malignancy in children. The conventional therapeutic modalities are mostly ineffective and thus new therapeutic strategies for malignant neuroblastoma are urgently warranted. We examined the synergistic efficacy of combination of sorafenib (SF) and genistein (GST) in human malignant neuroblastoma SK-N-DZ (N-Myc amplified) and SH-SY5Y (N-Myc non-amplified) cell lines. MTT assay showed dose-dependent decrease in cell viability and the combination therapy more prominently inhibited the cell proliferation in both cell lines than either treatment alone. Apoptosis was confirmed morphologically by Wright staining. Flow cytometric analysis of cell cycle phase distribution and Annexin V-FITC/PI staining showed increase in subG1 DNA content and early apoptosis, respectively, after treatment with the combination of drugs. Apoptosis was further confirmed by scanning electron microscopy. Combination therapy showed activation of caspase-8, cleavage of Bid to tBid, increase in p53 and p21 expression, down regulation of anti-apoptotic Mcl-1, and increase in Bax:Bcl-2 ratio to trigger apoptosis. Down regulation of MDR, hTERT, N-Myc, VEGF, FGF-2, NF-κB, p-Akt, and c-IAP2 indicated suppression of angiogenic and survival pathways. Mitochondrial release of cytochrome c and Smac into cytosol indicated involvement of mitochondia in apoptosis. Increases in proteolytic activities of calpain and caspase-3 were also confirmed. Our results suggested that combination of SF and GST inhibited angiogenic and survival factors and increased apoptosis via receptor and mitochondria mediated pathways in both neuroblastoma SK-N-DZ and SH-SY5Y cell lines. Thus, this combination of drugs could be a potential therapeutic strategy against human malignant neuroblastoma cells having N-Myc amplification or non-amplification.

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Section: Discussionmentioning

confidence: 94%

Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification

et al. 2009

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“…After each time point, cells were harvested, counted and prepared for monoparametric DNA staining with propidium iodide (PI) accordingly to the procedure already described (Di Francesco et al, 2007). Pgp protein was evaluated in both paired cellular models using indirect immunofluorescence flow cytometry techniques as already described in Tognon et al (2005).…”

Section: Cell Cycle Studies and P-glycoprotein Detectionmentioning

confidence: 99%

“…Whereas the broad biologic effects of classic retinoids are mediated by retinoic acid receptors, and involve G1 arrest, apoptosis and/or cell differentiation (Melino et al, 1997;Fontana and Rishi, 2002), the antiproliferative and apoptogenic activity of RRMs is independent of receptor-mediated transcriptional activity (Lotan, 2003;Zhao and Spanjaard, 2003). Among these novel drugs, we have focused on ST1926, a strong pro-apoptotic agent endowed with antitumor activity in many models including NB and showing a better pharmacological profile than the RRMs' prototype, CD437 (Di Francesco et al, 2007;Cincinelli et al, 2003;Zuco et al, 2004;Garattini et al, 2004;Gaetano et al, 1991). During our studies on ST1926-mediated effects in NB, we selected the ST1926-resistant subline rAS-ST by continuous treatment of the NB cell line SK-N-AS with the novel retinoid.…”

Section: Introductionmentioning

confidence: 98%

Resistance to the atypical retinoid ST1926 in SK-N-AS cells selected the subline rAS-ST with enhanced sensitivity to ATRA mediated by not conventional mechanisms: DNA damage, G2 accumulation and late telomerase inhibition

Francesco

Cusano

Franzese

et al. 2015

Toxicology in Vitro

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“…The cellular (CACA) and subcellular (SACA) variants of the alkaline COMET assays were done as described (25) and according to Kasamatsu et al (26), respectively. For each sample, 100 cells or nuclei were acquired using a Zeiss fluorescence microscope connected to an Ultrak CCD black-and-white camera.…”

Section: Methodsmentioning

confidence: 99%

Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

Valli¹,

Paroni²,

Francesco

et al. 2008

Molecular Cancer Therapeutics

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Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (;-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlying the antileukemic activity of RRMs in NB4 and other AML cell lines. In accordance with the S-phase specificity of the cytotoxic and antiproliferative responses of AML cells to RRMs, increases in DSBs are maximal during the S phase of the cell cycle. Induction of DSBs precedes inhibition of DNA replication and is associated with rapid activation of ataxia telangectasia mutated, ataxia telangectasia RAD3-related, and DNAdependent protein kinases with subsequent stimulation of the p38 mitogen-activated protein kinase. Inhibition of ataxia telangectasia mutated and DNA-dependent protein kinases reduces phosphorylation of H2AX. Cells defective for homologous recombination are particularly sensitive to ST1926, indicating that this process is important for the protection of cells from the RRM-dependent DNA damage and cytotoxicity. [Mol Cancer Ther 2008;7(9):2941 -54]

show abstract

The novel atypical retinoid ST1926 is active in ATRA resistant neuroblastoma cells acting by a different mechanism

Cited by 30 publications

References 25 publications

Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification

Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification

Resistance to the atypical retinoid ST1926 in SK-N-AS cells selected the subline rAS-ST with enhanced sensitivity to ATRA mediated by not conventional mechanisms: DNA damage, G2 accumulation and late telomerase inhibition

Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity

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