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Picoplatin overcomes resistance to cell toxicity in small-cell lung cancer cells previously treated with cisplatin and carboplatin.

Tang CH, Parham C, Shocron E, McMahon G, Patel N - Cancer Chemother. Pharmacol. (2010)

Bottom Line: Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment.Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance.The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.

View Article: PubMed Central - PubMed

Affiliation: Poniard Pharmaceuticals, Inc, South San Francisco, CA, USA. chi_hui.tang@yahoo.com

ABSTRACT

Purpose: Picoplatin is a new generation platinum designed to overcome platinum resistance. The goal of this study was to assess picoplatin anti-tumor activity and measure various cellular parameters in small-cell lung cancer (SCLC) cells resistant to cell killing by cisplatin and carboplatin.

Methods: We developed several platinum-resistant SCLC cell lines to evaluate picoplatin activity and drug resistance mechanisms in vitro. Drug cytotoxicity was measured by MTS assay. Total cellular platinum accumulation was measured by inductively coupled plasma mass spectrometry (ICP-MS). Whole genome gene expression profiling was carried out by microarray analysis.

Results: Picoplatin retained significant cytotoxic activity in platinum-resistant SCLC lines compared to cisplatin and carboplatin. Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment. Gene expression analyses revealed substantial differences in gene expression and highlighted specific annotation clusters in carboplatin-resistant cells. In addition, a similar gene expression pattern was observed in picoplatin-treated carboplatin-resistant and parental cells.

Conclusions: Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance. The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.

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Dendrogram of two-dimensional hierarchical clustering analysis of differential expression by treatment. The heatmap indicates log2 fold change of all sample replicates relative to the average across arrays (aveA) for genes that were differentially expressed in any of the treatment contrasts; red upregulated and green downregulated. Due to the large basal gene expression differences between carboplatin-resistant and parental cells, fold changes were calculated relative to the no treatment group of the respective cell line to discern treatment-induced changes in each line. The line height of dendrograms indicates the Euclidean average distance between clusters. Treatment groups are represented by color below the treatment dendrogram on the x-axis (black parental, no treat; red parental, carbo; green parental, pico; dark blue carboR, no treat; light blue carboR, carbo; pink carboR, pico)
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Fig3: Dendrogram of two-dimensional hierarchical clustering analysis of differential expression by treatment. The heatmap indicates log2 fold change of all sample replicates relative to the average across arrays (aveA) for genes that were differentially expressed in any of the treatment contrasts; red upregulated and green downregulated. Due to the large basal gene expression differences between carboplatin-resistant and parental cells, fold changes were calculated relative to the no treatment group of the respective cell line to discern treatment-induced changes in each line. The line height of dendrograms indicates the Euclidean average distance between clusters. Treatment groups are represented by color below the treatment dendrogram on the x-axis (black parental, no treat; red parental, carbo; green parental, pico; dark blue carboR, no treat; light blue carboR, carbo; pink carboR, pico)

Mentions: In order to evaluate the gene expression changes between treatments, an unsupervised hierarchical clustering analysis was performed (Fig. 3). Because of the substantial basal differences between carboplatin-resistant and parent cells, treatment-induced fold changes were calculated relative to the no treatment expression levels from their respective cell lines. As expected, treatment replicates generally clustered well (Fig. 3, x-axis dendrogram). Interestingly, clustering of treatment-induced differential expression also resulted in clustering of picoplatin-treated parental and carboplatin-resistant samples, suggesting that picoplatin elicits a similar response in both parental and carboplatin-resistant cells but is distinct from that of carboplatin. Carboplatin-treated parental samples clustered together whereas carboplatin-treated carboplatin-resistant replicates clustered loosely with no treatment replicates of both lines, suggesting that gene expression was not substantially affected by selection drug treatment in carboplatin-resistant cells. This is likely explained by the relative lack of differential gene expression after carboplatin treatment of carboplatin-resistant cells.Fig. 3


Picoplatin overcomes resistance to cell toxicity in small-cell lung cancer cells previously treated with cisplatin and carboplatin.

Tang CH, Parham C, Shocron E, McMahon G, Patel N - Cancer Chemother. Pharmacol. (2010)

Dendrogram of two-dimensional hierarchical clustering analysis of differential expression by treatment. The heatmap indicates log2 fold change of all sample replicates relative to the average across arrays (aveA) for genes that were differentially expressed in any of the treatment contrasts; red upregulated and green downregulated. Due to the large basal gene expression differences between carboplatin-resistant and parental cells, fold changes were calculated relative to the no treatment group of the respective cell line to discern treatment-induced changes in each line. The line height of dendrograms indicates the Euclidean average distance between clusters. Treatment groups are represented by color below the treatment dendrogram on the x-axis (black parental, no treat; red parental, carbo; green parental, pico; dark blue carboR, no treat; light blue carboR, carbo; pink carboR, pico)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102205&req=5

Fig3: Dendrogram of two-dimensional hierarchical clustering analysis of differential expression by treatment. The heatmap indicates log2 fold change of all sample replicates relative to the average across arrays (aveA) for genes that were differentially expressed in any of the treatment contrasts; red upregulated and green downregulated. Due to the large basal gene expression differences between carboplatin-resistant and parental cells, fold changes were calculated relative to the no treatment group of the respective cell line to discern treatment-induced changes in each line. The line height of dendrograms indicates the Euclidean average distance between clusters. Treatment groups are represented by color below the treatment dendrogram on the x-axis (black parental, no treat; red parental, carbo; green parental, pico; dark blue carboR, no treat; light blue carboR, carbo; pink carboR, pico)
Mentions: In order to evaluate the gene expression changes between treatments, an unsupervised hierarchical clustering analysis was performed (Fig. 3). Because of the substantial basal differences between carboplatin-resistant and parent cells, treatment-induced fold changes were calculated relative to the no treatment expression levels from their respective cell lines. As expected, treatment replicates generally clustered well (Fig. 3, x-axis dendrogram). Interestingly, clustering of treatment-induced differential expression also resulted in clustering of picoplatin-treated parental and carboplatin-resistant samples, suggesting that picoplatin elicits a similar response in both parental and carboplatin-resistant cells but is distinct from that of carboplatin. Carboplatin-treated parental samples clustered together whereas carboplatin-treated carboplatin-resistant replicates clustered loosely with no treatment replicates of both lines, suggesting that gene expression was not substantially affected by selection drug treatment in carboplatin-resistant cells. This is likely explained by the relative lack of differential gene expression after carboplatin treatment of carboplatin-resistant cells.Fig. 3

Bottom Line: Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment.Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance.The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.

View Article: PubMed Central - PubMed

Affiliation: Poniard Pharmaceuticals, Inc, South San Francisco, CA, USA. chi_hui.tang@yahoo.com

ABSTRACT

Purpose: Picoplatin is a new generation platinum designed to overcome platinum resistance. The goal of this study was to assess picoplatin anti-tumor activity and measure various cellular parameters in small-cell lung cancer (SCLC) cells resistant to cell killing by cisplatin and carboplatin.

Methods: We developed several platinum-resistant SCLC cell lines to evaluate picoplatin activity and drug resistance mechanisms in vitro. Drug cytotoxicity was measured by MTS assay. Total cellular platinum accumulation was measured by inductively coupled plasma mass spectrometry (ICP-MS). Whole genome gene expression profiling was carried out by microarray analysis.

Results: Picoplatin retained significant cytotoxic activity in platinum-resistant SCLC lines compared to cisplatin and carboplatin. Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment. Gene expression analyses revealed substantial differences in gene expression and highlighted specific annotation clusters in carboplatin-resistant cells. In addition, a similar gene expression pattern was observed in picoplatin-treated carboplatin-resistant and parental cells.

Conclusions: Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance. The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.

Show MeSH
Related in: MedlinePlus