Abstract 5414: Targeting prostate cancer through a combination of Polo-like kinase inhibitors and histone deacetylase inhibitors

2010 ◽  
Author(s):  
Michel D. Wissing ◽  
Nadine Rosmus ◽  
Matthew Gonzalez ◽  
Hans Hammers ◽  
Michael A. Carducci ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitors

scholarly journals Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Laura Kasman ◽  
Georgiana Onicescu ◽  
Christina Voelkel-Johnson
Keyword(s):  
Prostate Cancer ◽  
Gene Therapy ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Chemotherapeutic Agents ◽  
Viral Gene ◽  
Castration Resistant Prostate Cancer ◽  
Cmv Promoter ◽  
Castration Resistant ◽  
Adenoviral Delivery

Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.

Effect of epigenetic modulation on interleukin-6 (IL-6) gene expression with adjuvant selenomethionine (Se-Met) with imatinib mesylate (IM) in remission of chronic myelogenous leukemia (CML-cp) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17022-e17022
Author(s):  
Eugene McPherson
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitors ◽  
Regulation Of Gene Expression ◽  
Myelogenous Leukemia ◽  
Abl Tyrosine Kinase ◽  
Nfkb Activation ◽  
Epigenetic Modulation

e17022 Background: Histone deacetylase (HDAC) are enzymes involved remodeling chromatin and epigenetic regulation of gene expression. Histone deacetylase inhibitors (HDACI) can reverse aberrant epigenetic changes in CML stem cells. BCR-abl tyrosine kinase inhibitors IM is effective in inducing remission in CML-cp patients but residual leukemia stem cells (LSC) may give rise to resistance and relapse. Pan-HDACI may arrest this with downregulation of IL-6, and NFkb activation when adjuvant Se-Met is combined with IM. Methods: CML-cp , CML-bc cases were presented with evidence of overexpression of BCR-abl fusion protein reported previously in elderly patients. A 91 YOF with CML-cp , subclinical hypothyroidism with elevated IL-6, CRP, sIL-2R, VEGF, NFkb, and IGF-1 was treated for seven years with adjuvant Se-Met, IM and levothyroxine ith normalization, minmal toxicity and extended trending down of IL-6, CRP,sIL-2R. Results: After seven years of adjuvant therapy with Se-Met, IM, and Levothyroxine a significant reduction of IL-6, CRP of 9.8075 down from 30.783 mg/L. Subsequuent normalization of the other pro-inflammatory cytokines were normalized. Conclusions: HDACI activity expressed in synergism of Se-Met with IM and Levothyroxine may lower the apoptotic threshold in CML-cp stem cells decreasing BCR-abl expression and rescuing quiescent progenitor cells that may prolong remission and decrease disease relapse.

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