Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells

Nguyen, Dao M.; Schrump, William D.; Chen, G. Aaron; Tsai, Wilson; Nguyen, Phuongmai; Trepel, Jane B.; Schrump, David S.

doi:10.1158/1078-0432.ccr-0901-3

Cited by 70 publications

(60 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since DP as well as apicidin induce p21 expression via PKC signal pathways (Han et al, 2001;Nguyen et al, 2004), additional experiments were performed to ascertain if DP augmented TFPI-2 expression via similar Representative results of IHC analysis of TFPI-2 expression in untreated cancer cell lines. Panels a-h: H460, CALU-6, H596, A549, H358, SK-Lu-1, H417, and H526 lung cancer cell lines, respectively.…”

Section: Regulation Of Tfpi-2 Expression In Cancer Cellsmentioning

confidence: 99%

Sequential 5-Aza 2′-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells

et al. 2005

View full text Add to dashboard Cite

Section: Regulation Of Tfpi-2 Expression In Cancer Cellsmentioning

confidence: 99%

Sequential 5-Aza 2′-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells

et al. 2005

View full text Add to dashboard Cite

“…There is growing evidence that Sp1 is overexpressed in human malignancies (Hosoi et al, 2004;Yao et al, 2004), and that Sp1 modulates growth and metastasis of cancer cells, in part, by regulating expression of a variety of cell-cycle-related genes, as well as vascular endothelial growth factor (Pore et al, 2004;Safe and Abdelrahim, 2005). Of particular interest in this regard, are recent data indicating that HDAC inhibitors such as DP induce p21 expression via activation of Sp1 (Nguyen et al, 2004). The present study was undertaken to investigate the functional relevance of Sp1 with regard to CTCF/BORIS-mediated regulation of NY-ESO-1 expression in lung cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Dynamic transcriptional regulatory complexes including BORIS, CTCF and Sp1 modulate NY-ESO-1 expression in lung cancer cells

et al. 2007

View full text Add to dashboard Cite

Previously, we reported that the paralogous zinc-finger proteins -CTCF and brother of the regulator of imprinted sites (BORIS), directly contribute to transcriptional regulation of NY-ESO-1 in lung cancer cells. To further examine mechanisms that mediate expression of this cancer-testis gene, we performed software-guided analysis of the NY-ESO-1 promoter region, which revealed several potential Sp1-binding motifs. Sequential 5-aza-2 0 deoxycytidine/depsipeptide FK228 treatment markedly induced BORIS expression and enhanced nuclear translocation of Sp1 in lung cancer cells. Transient transfection assays using promoter-reporter constructs, as well as gel-shift and chromatin immunoprecipitation experiments revealed that NY-ESO-1 promoter activity coincided with occupancy of the proximal Sp1-binding site in lung cancer cells. Mutations within the Sp1 recognition sequence specifically eliminated binding of Sp1 to this motif in vitro, and markedly diminished NY-ESO-1 promoter activity in vivo. siRNA-mediated inhibition of Sp1 expression decreased NY-ESO-1 promoter activity, whereas knock down of CTCF expression augmented NY-ESO-1 transcription in lung cancer cells. Co-immunoprecipitation experiments indicated that Sp1 physically interacts with BORIS but not with CTCF in vivo. Collectively, these findings suggest that BORIS recruits Sp1 to mediate de-repression of NY-ESO-1 during pulmonary carcinogenesis.

show abstract

“…Activation of NF-kB transcriptional activity and upregulation of p21 gene expression are frequently observed following HDACI treatments in cancer cells (Burgess et al, 2001;Dai et al, 2003;Mayo et al, 2003). Histone deacetylase inhibitor-mediated activation of NF-kB activity and/or upregulation of p21 gene expression have actually been shown to impede drug-induced apoptosis (Burgess et al, 2001;Mayo et al, 2003;Nguyen et al, 2003Nguyen et al, , 2004Rundall et al, 2004;Maxhimer et al, 2005). In fact, inhibition of HDACIinduced NF-kB activation by pharmacologic inhibitors of IkB kinase inhibitor (IKK) or by overexpression of kinase-resistant IkB resulted in substantial induction of apoptosis of HDACI-treated cells (Rundall et al, 2004;Maxhimer et al, 2005).…”

mentioning

confidence: 99%

“…Maxhimer et al (2005) have shown that the PKC inhibitor Calphostin C (CC) completely abrogated TSA-mediated NF-kB activation in cultured thoracic cancer cells and this was associated with profound induction of apoptosis following treatment with CC þ TSA drug combination. Moreover, Grant and his co-workers (Rosato et al, 2002;Rahmani et al, 2003a, b) as well as our group (Nguyen et al, 2003(Nguyen et al, , 2004 have published multiple reports that described the synergistic interactions between HDACIs and different kinase inhibitors (for instance, Flavopiridol or LY294002) to induce massive apoptosis in leukaemic or thoracic cancer cells in vitro. These findings support further preclinical and clinical development of targeted therapeutic strategies that combine inhibition of either NF-kB or PI3K or PKC signallings with HDACIs by using clinically relevant pharmacologies.…”

mentioning

confidence: 99%

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

et al. 2006

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-kB inhibitor) abrogates HDACI-induced transcriptional activation of NF-kB and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62 -10.0 mM) resulted in significant cell line-and dose-dependent growth inhibition (IC 50 values: 4.1 -6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5 -20-fold upregulation of transcriptional activity of NF-kB was substantially (50 -90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (o20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60 -90% of cells underwent apoptosis following exposure to combinations of VA þ kinase inhibitors. Kinase inhibitor-mediated suppression of NF-kB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kB by Parthenolide drastically synergised with VA to induce apoptosis (VA þ Parthenolide: 60 -90% compared to o20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-kB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.

show abstract

Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells

Abstract: Conclusions: FLA abrogates DP-mediated induction of p21 expression, in part, via inhibition of protein kinase C signaling and markedly potentiates the cytotoxic effects of DP in MPM cells.

Cited by 70 publications

References 43 publications

Sequential 5-Aza 2′-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells

Sequential 5-Aza 2′-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells

Dynamic transcriptional regulatory complexes including BORIS, CTCF and Sp1 modulate NY-ESO-1 expression in lung cancer cells

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Contact Info

Product

Resources

About