Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

Zuco, Valentina; Zanchi, Chiara; Cassinelli, Giuliana; Lanzi, Cinzia; Supino, Rosanna; Pisano, Claudio; Zanier, Romina; Giordano, Vincenzo; Garattini, Enrico; Zunino, Franco

doi:10.1038/sj.cdd.4401304

Cited by 53 publications

(72 citation statements)

References 29 publications

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“…Cells were rinsed twice with PBS, added with 0.1 mM sodium orthovanadate and lysed in hot 7 sample buffer [11]. After determination of protein concentration, whole-cell extracts were separated by SDS polyacrylamide gel electrophoresis (PAGE) and transferred onto nitrocellulose filters.…”

Section: Western Blot Analysismentioning

confidence: 99%

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Zuco¹,

Supino²,

Favini³

et al. 2010

Biochemical Pharmacology

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ST1968 (namitecan), a novel 7-modified hydrophilic camptothecin, was found to be effective against tumor models relatively resistant to topotecan and irinotecan. Based on this observation, this study was designed to investigate the cellular and antitumor effects of ST1968 in a subline of A431, squamous cell carcinoma, selected for resistance to topotecan (A431/TPT). This model was characterized by a slow growth rate, associated with down-regulation of EGFR and topoisomerase I. In contrast to other camptothecins (SN38 and gimatecan), ST1968 was able to overcome almost completely the resistance at cellular level. The cellular pharmacokinetics indicated a comparable accumulation and retention of ST1968 in sensitive and resistant cells, in spite of expression of the efflux transporter, P-glycoprotein, in resistant cells. The uptake and retention of topotecan was dramatically reduced in both tumor cell lines, but more evident in the resistant one. In contrast to topotecan, ST1968 retained an outstanding efficacy in vivo against the resistant tumor (A431/TPT). The results are consistent with the interpretation that ST1968 was able to overcome the most relevant mechanisms associated with the development of topotecan resistance (i.e., slow proliferation and target downregulation) owing to its peculiar pharmacokinetic behaviour.

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Section: Western Blot Analysismentioning

confidence: 99%

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Zuco¹,

Supino²,

Favini³

et al. 2010

Biochemical Pharmacology

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“…Other RRMs have been described and, in general, they show enhanced efficacy with fewer side effects. They frequently kill cells via an apoptotic mechanism (Bayon et al, 2003;Garattini et al, 2004a, b;Lopez-Hernandez et al, 2004;Zuco et al, 2004).…”

Section: Retinoid-related Moleculesmentioning

confidence: 99%

“…Some heteroarotinoids have been reported to suppress cell survival via retinoid receptor-independent mechanisms, while others appear to require receptor function (Spruce et al, 1991;Benbrook et al, 1998;Chun et al, 2003;Liu et al, 2004). Several RRMs, including N-(4-hydroxyphenyl) retinamide (fenretinide) and 6-[3-(-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), ST1926, MM002, MM11453 and MX-3350-1, have been studied in several systems (Dawson et al, 2001;Garattini et al, 2004a, b;Zuco et al, 2004). These agents promote apoptosis in a variety of tumor cell types and frequently display reduced toxicity compared to classical retinoids.…”

Section: Introductionmentioning

confidence: 99%

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

2005

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acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)-or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR-or RXR receptorselective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclindependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.

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“…Western Blot Analysis Western blot analysis of total cell lysates was done as described previously (20). Briefly, adherent and floating cells were collected and rinsed with cold PBS plus 0.1 mmol/L sodium orthovanadate.…”

Section: Mutational Analysis Of Egfr Pten and P53mentioning

confidence: 99%

Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds

Benedetti

Perego

Beretta

et al. 2008

Molecular Cancer Therapeutics

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Because cytotoxic stress elicits various signaling pathways that may be implicated in cell survival or cell death, their alterations may have relevance in the development of platinum-resistant phenotype. Thus, in the present study, we investigated cell response to the epidermal growth factor receptor (EGFR) inhibitor gefitinib of ovarian carcinoma cell lines, including cells selected for resistance to cisplatin (IGROV-1/Pt1) and oxaliplatin (IGROV-1/OHP). Resistant sublines exhibited a marked decrease in sensitivity to gefitinib and resistance to apoptosis. Gefitinib was capable of inhibiting the phosphorylation of EGFR in all the studied cell lines. The Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, which act downstream of EGFR, were constitutively active in the three cell lines, but phospho-ERK1/2 levels were increased in the two resistant sublines. This feature was associated with reduced sensitivity to the MEK1/2 inhibitor U0126. Pretreatment of resistant cells with U0126 resulted in restoration of sensitivity to gefitinib. Gefitinib was more effective in inhibiting ERK1/ 2 and Akt phosphorylation in IGROV-1 cells than in IGROV-1/OHP and IGROV-1/Pt1 cells. Phospho-p38 was up-regulated in the resistant sublines, indicating the concomitant activation of distinct mitogen-activated protein kinases. The up-regulation of phospho-p38 was associated with a peculiar localization of EGFR, which, in resistant sublines, was mainly internalized. In conclusion, our results indicate that the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGFR resulting in a reduced cellular response to gefitinib.

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Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

Cited by 53 publications

References 29 publications

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds

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