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A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors.

Tula-Sanchez AA, Havas AP, Alonge PJ, Klein ME, Doctor SR, Pinkston W, Glinsmann-Gibson BJ, Rimsza LM, Smith CL - Cancer Biol. Ther. (2013)

Bottom Line: While the initial treatment strategy is highly effective, relapse occurs in 40% of cases.Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation.PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology; College of Pharmacy; University of Arizona; Tucson, AZ USA.

ABSTRACT
Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G 2/M arrest and apoptosis and resistance by reversible G 1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL.

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Related in: MedlinePlus

Figure 2. The cytostatic response to PXD101. SUDHL4 (A and B), SUDHL8 (C and D), and U2932 (E and F) cells were treated with PXD101 at the IC50 concentrations determined for each as shown in Table 1. At 0, 24, 48, and 72 h treatment cells were harvested and subjected to Annexin V/PI assay (A, C, and E) or cell cycle analysis (B, D, and F). The graphs shown represent the results of 3–4 independent experiments. Error bars represent SEM.
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Figure 2: Figure 2. The cytostatic response to PXD101. SUDHL4 (A and B), SUDHL8 (C and D), and U2932 (E and F) cells were treated with PXD101 at the IC50 concentrations determined for each as shown in Table 1. At 0, 24, 48, and 72 h treatment cells were harvested and subjected to Annexin V/PI assay (A, C, and E) or cell cycle analysis (B, D, and F). The graphs shown represent the results of 3–4 independent experiments. Error bars represent SEM.

Mentions: In contrast, PXD101 induced no significant apoptosis relative to vehicle-treated controls in SUDHL4 and SUDHL8 cells (Fig. 2A and C). In the ABC-type line U2932 a greater amount of apoptosis was observed involving about 25% of cells as shown in Figure 2E. Cell cycle analysis showed that PXD101 triggers a cytostatic response in these lines characterized by accumulation of cells in the G1 phase of the cell cycle (Fig. 2B, D, and F). At least 75% of cells accumulate in G1 by 24–48 h treatment which is largely maintained with further drug exposure, indicating that PXD101 induces G1 arrest in these cell lines.


A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors.

Tula-Sanchez AA, Havas AP, Alonge PJ, Klein ME, Doctor SR, Pinkston W, Glinsmann-Gibson BJ, Rimsza LM, Smith CL - Cancer Biol. Ther. (2013)

Figure 2. The cytostatic response to PXD101. SUDHL4 (A and B), SUDHL8 (C and D), and U2932 (E and F) cells were treated with PXD101 at the IC50 concentrations determined for each as shown in Table 1. At 0, 24, 48, and 72 h treatment cells were harvested and subjected to Annexin V/PI assay (A, C, and E) or cell cycle analysis (B, D, and F). The graphs shown represent the results of 3–4 independent experiments. Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926892&req=5

Figure 2: Figure 2. The cytostatic response to PXD101. SUDHL4 (A and B), SUDHL8 (C and D), and U2932 (E and F) cells were treated with PXD101 at the IC50 concentrations determined for each as shown in Table 1. At 0, 24, 48, and 72 h treatment cells were harvested and subjected to Annexin V/PI assay (A, C, and E) or cell cycle analysis (B, D, and F). The graphs shown represent the results of 3–4 independent experiments. Error bars represent SEM.
Mentions: In contrast, PXD101 induced no significant apoptosis relative to vehicle-treated controls in SUDHL4 and SUDHL8 cells (Fig. 2A and C). In the ABC-type line U2932 a greater amount of apoptosis was observed involving about 25% of cells as shown in Figure 2E. Cell cycle analysis showed that PXD101 triggers a cytostatic response in these lines characterized by accumulation of cells in the G1 phase of the cell cycle (Fig. 2B, D, and F). At least 75% of cells accumulate in G1 by 24–48 h treatment which is largely maintained with further drug exposure, indicating that PXD101 induces G1 arrest in these cell lines.

Bottom Line: While the initial treatment strategy is highly effective, relapse occurs in 40% of cases.Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation.PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology; College of Pharmacy; University of Arizona; Tucson, AZ USA.

ABSTRACT
Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G 2/M arrest and apoptosis and resistance by reversible G 1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL.

Show MeSH
Related in: MedlinePlus