Bortezomib‐induced sensitization of malignant human glioma cells to vorinostat‐induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl‐1 cleavage, and DNA damage

Premkumar, Daniel R.; Jane, Esther P.; Agostino, Naomi R.; DiDomenico, Joseph D.; Pollack, Ian F.

doi:10.1002/mc.21835

Cited by 57 publications

(66 citation statements)

References 53 publications

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“…1C). These results are in agreement with those of previous studies using diverse malignant cell types and various combinations of HDACIs and PIs (15,22).…”

Section: Discussionsupporting

confidence: 93%

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Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Abaza

Bahman

Al‐Attiyah

2014

International Journal of Molecular Medicine

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Abstract.Although the therapeutic efficacy of valproic acid (VPA) has been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical utility. The present study focused on the development of combined molecular targeted therapies using VPA and proteasome inhibitors (PIs: MG132, PI-1 and PR-39) to determine whether this combination of treatments has synergistic anticancer and chemosensitizing effects against colorectal cancer. Furthermore, the potential molecular mechanisms of action of the VPA/PI combinations were evaluated. The effects of VPA in combination with PIs on the growth of colorectal cancer cells were assessed with regard to proliferation, cell cycle, apoptosis, reactive oxygen species (ROS) generation and the expression of genes that control the cell cycle, apoptosis and pro-survival/stress-related pathways. Treatment with combinations of VPA and PIs resulted in an additive/synergistic decrease in colorectal cancer cell proliferation compared to treatment with VPA or PIs alone. The combination treatment was associated with a synergistic increase in apoptosis and in the number of cells arrested in the S phase of the cell cycle. These events were associated with increased ROS generation, pro-apoptotic gene expression and stress-related gene expression. These events were also associated with the decreased expression of anti-apoptotic genes and pro-survival genes. The combination of VPA with MG132 or PI-1 enhanced the chemosensitivity of the SW1116 (29-185-fold) and SW837 (50-620-fold) colorectal cancer cells. By contrast, the combination of VPA/PR-39 induced a pronounced increase in the chemosensitivity of the SW837 (16-54-fold) colorectal cancer cells. These data provide a rational basis for the clinical use of this combination therapy for the treatment of colorectal cancer. IntroductionHistone deacetylase (HDAC) activity has been shown to be upregulated in cancer cells. It is considered that this upregulation results in the repression of tumor suppressor gene products, such as p53, rendering HDACs an attractive drug target. In cell culture models, HDAC inhibitors (HDACIs) have been shown to decrease proliferation rates, induce apoptosis and induce autophagy-related cell death in several cancer cell lines. Due to their relative specificity toward cancer cells, HDACIs represent a new class of cancer treatment agents that are generally well tolerated (1).Short-chain fatty acids, such as butyric and valproic acid (VPA) were the first HDACIs to be identified as tumor growth inhibitors and inducers of apoptosis both in vitro and in vivo. However, they were found to have low potency (2). Despite such weak in vitro activity, the anticancer effects of VPA have been investigated in preclinical models of skin, breast, colon, prostate and small cell lung cancer, and the drug is currently being used in phase I-III clinical trials (3). However, the therapeutic doses of VPA are very high and cause side-effects severe enough to limit its usage.Despite ...

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“…1C). These results are in agreement with those of previous studies using diverse malignant cell types and various combinations of HDACIs and PIs (15,22).…”

Section: Discussionsupporting

confidence: 93%

“…ROS have been implicated in HDAC and PI-induced cytotoxicity in a number of different types of malignancies (15). Thus, the effects of VPA, PIs, or a combination of VPA and PIs on ROS generation in the human SW837 colorectal cancer cells were examined.…”

Section: Inhibition Of Hdac and 26s Proteasome Activities And Induc Tmentioning

confidence: 99%

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Abaza

Bahman

Al‐Attiyah

2014

International Journal of Molecular Medicine

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“…Given the importance of epigenetics in oncogenic transformation, many of these molecules are aimed at treating tumours [26,96]. One of the most studied is Vorinostat (suberoylanilide hydroxamic acid), a histone deacetylase inhibitor that is currently FDA-approved for the treatment of leukemia but is also being tested in brain tumor clinical trials [97,98]. Vorinostat activates the expression of genes involved in cell differentiation by inhibiting HDACs, which have been found to be overexpressed in tumours [99].…”

Section: Small Moleculesmentioning

confidence: 99%

“…Vorinostat activates the expression of genes involved in cell differentiation by inhibiting HDACs, which have been found to be overexpressed in tumours [99]. Vorinostat is being tested for its single-agent activity and also in combination with compounds like the proteasome inhibitor Bortezomib where it has been found to induce sensitization of malignant human glioma cells to apoptosis [98].…”

Section: Small Moleculesmentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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“…The complexity of the interactions between cell surface receptors and downstream signaling targets has called into question the clinical utility of blocking any target in isolation, and the results of single agent-based strategies have to date been disappointing in patients with glioma. 2,4 Combination approaches can enhance ABT-737-induced glioma cell death, including use with the proteasomal inhibitor bortezomib, 34 the survivin inhibitor YM-155, 30 the PI3K/Akt inhibitor NVP-BKM120, 31 the histone deacetylase inhibitor vorinostat, 35 the alkylating agent temozolomide, 36 or the death receptor ligand TRAIL. 37 We performed a screen of ABT-737 in combination with other signaling inhibitors used at clinically achievable doses; combination of ABT-737 and cucurbitacin-I promoted apoptosis in malignant human glioma cell lines.…”

Section: Introductionmentioning

confidence: 99%

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Premkumar¹,

Jane

Pollack

2014

Cancer Biology & Therapy

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Abbreviations: BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; MTS,[3][4]]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium; FITC, fluorescein isothiocyanate; NF-kB, nuclear factor kB; PI3K, Phosphatidylinositol 3-Kinase; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; PDGFR, platelet derived growth factor receptor; TBS, Tris-buffered saline; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; PI, propidium iodide.Because STAT signaling is commonly activated in malignant gliomas as a result of constitutive EGFR activation, strategies for inhibiting the EGFR/JAK/STAT cascade are of significant interest. We, therefore, treated a panel of established glioma cell lines, including EGFR overexpressors, and primary cultures derived from patients diagnosed with glioblastoma with the JAK/STAT inhibitor cucurbitacin-I. Treatment with cucurbitacin-I depleted p-STAT3, p-STAT5, p-JAK1 and p-JAK2 levels, inhibited cell proliferation, and induced G2/M accumulation, DNA endoreduplication, and multipolar mitotic spindles. Longer exposure to cucurbitacin-I significantly reduced the number of viable cells and this decrease in viability was associated with cell death, as confirmed by an increase in the subG1 fraction. Our data also demonstrated that cucurbitacin-I strikingly downregulated Aurora kinase A, Aurora kinase B and survivin. We then searched for agents that exhibited a synergistic effect on cell death in combination with cucurbitacin-I. We found that cotreatment with cucurbitacin-I significantly increased Bcl -2/Bcl -xL family member antagonist ABT-737-induced cell death regardless of EGFR/PTEN/p53 status of malignant human glioma cell lines. Although >50% of the cucurbitacin-I plus ABT-737 treated cells were annexin V and propidium iodide positive, PARP cleavage or caspase activation was not observed. Pretreatment of z-VAD-fmk, a pan caspase inhibitor did not inhibit cell death, suggesting a caspaseindependent mechanism of cell death. Genetic inhibition of Aurora kinase A or Aurora kinase B or survivin by RNA interference also sensitized glioma cells to ABT-737, suggesting a link between STAT activation and Aurora kinases in malignant gliomas.

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Bortezomib‐induced sensitization of malignant human glioma cells to vorinostat‐induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl‐1 cleavage, and DNA damage

Cited by 57 publications

References 53 publications

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

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