Steven Grant

Virginia Commonwealth University, Ричмонд, Virginia, United States

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Publications (443)2555.81 Total impact

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    ABSTRACT: Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose-response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line. To our best knowledge, this is the first ever three drug combinations study performed based on the original 4D dose-response surface formed by dose ranges of three drugs. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    Statistical Methods in Medical Research 03/2015; DOI:10.1177/0962280215574320 · 2.96 Impact Factor
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    Yun Dai, Steven Grant
    Autophagy 02/2015; DOI:10.1080/15548627.2014.998892 · 11.42 Impact Factor
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    ABSTRACT: The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with the ERBB1/ERBB2 inhibitor lapatinib to kill CNS tumor cells. In multiple CNS tumor cell types sorafenib and lapatinib interacted in a greater than additive fashion to cause tumor cell death. Tumor cells lacking PTEN, and anoikis or lapatinib resistant cells were as sensitive to the drug combination as cells expressing PTEN or parental cells, respectively. Similar data were obtained using regorafenib. Treatment of brain cancer cells with [sorafenib + lapatinib] enhanced radiation toxicity. The drug combination increased the numbers of LC3-GFP vesicles; this correlated with a reduction in endogenous LC3II, and p62 and LAMP2 degradation. Knock down of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, BCL-XL, or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 or activated mTOR was required to strongly suppress drug combination lethality. As both lapatinib and sorafenib are FDA approved agents, our data argue for further determination as to whether lapatinib and sorafenib is a useful glioblastoma therapy. J. Cell. Physiol. 230: 131-139, 2015. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2015; 230(1):131-139. DOI:10.1002/jcp.24689 · 3.87 Impact Factor
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    ABSTRACT: Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL+ leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph+ ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34+ CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34+ cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph+ ALL.
    Leukemia Research 11/2014; 39(1). DOI:10.1016/j.leukres.2014.10.009 · 2.69 Impact Factor
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    Chunrong Yu, Yun Dai, Paul Dent, Steven Grant
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    ABSTRACT: Interactions between the PKC and Chk1 inhibitor UCN-01 and pharmacologic MEK1/2 inhibitors (e.g., U0126, PD184352) were examined in Bcr/Abl(+) = human leukemia cells (K562, LAMA 84) sensitive and resistant to the Bcr/Abl kinase inhibitor STI571. Coexposure of K562 cells to UCN-01 (e.g., 100 nM) or U0126 (30 microM) resulted in a marked increase in mitochondrial injury (e.g., release of cytochrome c; loss of deltapsi(m)) and apoptosis. Similar results were obtained in other Bcr/Abl(+) cells (e.g., LAMA 84, BV-173) and with other MEK1/2 inhibitors (e.g., PD184352). Exposure of K562 cells to UCN-01 resulted in activation of ERK, an effect that was abrogated by co-administration of MEK1/2 inhibitors. Coadminstration of UCN-01 with U0126 produced multiple perturbations in signal transduction/cell cycle regulatory pathways, including diminished expression of Bcr/Abl, Mcl-1, cylin D(1), and activation of JNK and p34(cdc2). Coadministration of the JNK inhibitor SP600125 attenuated UCN-01/MEK inhibitor- associated lethality, suggesting a functional role for JNK activation in enhanced lethality. Finally, UCN-01 and MEK1/2 inhibitors effectively induced apoptosis in Bcr/Abl(+) cells (e.g., K562 and LAMA 84) overexpressing Bcr/Abl and resistant to STI571. These findings indicate that BcrAbl(+) leukemia cells are sensitive to a strategy combining UCN-01 with MEK/ERK inhibitors that simultaneously disrupts two signaling pathways.
    Cancer biology & therapy 10/2014; 1(6):674-82. DOI:10.4161/cbt.319 · 3.63 Impact Factor
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    ABSTRACT: B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined non-toxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin (Trx) system, with non-toxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione (GSH) levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. AUR interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle cell lymphoma (MCL) cells. Additionally, there was less toxicity toward normal B-cells. Low AUR concentrations inhibited Trx reductase (TrxR) activity, an effect significantly increased by BSO co-treatment. TrxR over-expression partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited NF-κB signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells over-expressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induce malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.
    Experimental Hematology 10/2014; 43(2). DOI:10.1016/j.exphem.2014.10.004 · 2.81 Impact Factor
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    ABSTRACT: AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs e.g., Vorinostat), which interrupt the DNA damage response (DDR), to kill p53-wild type or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knock-down significantly sensitized cells to HDACIs. While AZD1775 induced Chk1 activation, reflected by markedly increased Chk1 S296/S317/S345 phosphorylation leading to inhibitory T14 phosphorylation of cdc2/Cdk1, these compensatory responses were sharply abrogated by HDACIs. This was accompanied by premature mitotic entry, multiple mitotic abnormalities, and accumulation of early S-phase cells displaying increased newly replicated DNA, culminating in robust DNA damage and apoptosis. The regimen was active against patient-derived AML cells harboring either wild type or mutant p53, and various NGS-defined mutations. Primitive CD34(+)/CD123(+)/CD38(-) populations enriched for leukemia-initiating progenitors, but not normal CD34(+) hematopoietic cells, were highly susceptible to this regimen. Finally, combining AZD1775 with Vorinostat in AML murine xenografts significantly reduced tumor burden and prolonged animal survival. A strategy combining Wee1 with HDACI inhibition warrants further investigation in AML with poor prognostic genetic aberrations.Leukemia accepted article preview online, 06 October 2014. doi:10.1038/leu.2014.296.
    Leukemia 10/2014; DOI:10.1038/leu.2014.296 · 9.38 Impact Factor
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    ABSTRACT: Introduction: Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL). Areas covered: This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed. Expert opinion: The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.
    Expert Opinion on Pharmacotherapy 09/2014; 15(16):1-17. DOI:10.1517/14656566.2014.965142 · 2.86 Impact Factor
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    ABSTRACT: Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma [MM], indolent lymphoma, Waldenstrom's macroglobulinemia, and mantle cell lymphoma). Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m2 for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common non-hematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory MM or indolent non-Hodgkin's lymphoma. As the non-hybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.
    Clinical Cancer Research 09/2014; DOI:10.1158/1078-0432.CCR-14-0805 · 8.19 Impact Factor
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    ABSTRACT: Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor Carfilzomib (CFZ) were examined in non-Hodgkin's lymphoma models, including diffuse large B-cell (DLBCL), mantle cell (MCL) and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with CFZ and ricolinostat increased reactive oxygen species (ROS), while the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34+ cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by CFZ. shRNA knock-down of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced CFZ/ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to CFZ and ricolinostat also markedly down-regulated the cargo-loading protein HR23B. Moreover, HR23B knock-down significantly increased CFZ- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with CFZ and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that CFZ and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL.
    Molecular Cancer Therapeutics 09/2014; DOI:10.1158/1535-7163.MCT-14-0220 · 5.60 Impact Factor
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    ABSTRACT: Bim perturbations contribute to resistance to various standard and novel agents. Here we demonstrate that Bim plays an important functional role in bortezomib (btz) resistance in multiple myeloma (MM) cells, and that targeting Bim by combining histone deacetylase inhibitors (HDACIs e.g., SBHA) with BH3-mimetics (e.g., ABT-737) overcomes btz-resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas shRNA Bim knockdown conferred btz-resistance in Bim(hi) cells, adaptive btz-resistant cells displayed marked Bim down-regulation. SBHA up-regulated Bim, and when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed cultured and primary btz-resistant MM cells. These events were associated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. Interestingly, in Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for SBHA/ABT-737 to induce Bim expression and lethality. CQ also further enhanced SBHA/ABT-737 lethality in btz-resistant cells. Finally, SBHA failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) MEFs. Thus, Bim deficiency represents a novel mechanism of adaptive btz-resistance in MM cells, and Bim-targeting strategies combining HDACIs (which up-regulate Bim) and BH3-mimetics (which unleash Bim from anti-apoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.
    Blood 09/2014; 124(17). DOI:10.1182/blood-2014-03-564534 · 9.78 Impact Factor
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    ABSTRACT: Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.
    PLoS ONE 09/2014; 9(9):e103015. DOI:10.1371/journal.pone.0103015 · 3.53 Impact Factor
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    ABSTRACT: The present studies examined the toxic interaction between the non-coxib celecoxib derivative OSU-03012 and phosphodiesterase 5 (PDE5) inhibitors, and to determine the roles of endoplasmic reticulum stress response regulators in cell survival. PDE5 inhibitors interacted in a greater than additive fashion with OSU-03012 to kill parental glioma and stem-like glioma cells. Knock down of the endoplasmic reticulum stress response proteins IRE1 or XBP1 enhanced the lethality of OSU-03012, and of [OSU-03012 + PDE5 inhibitor] treatment. Pan-caspase and caspase 9 inhibition did not alter OSU-03012 lethality but did abolish enhanced killing in the absence of IRE1 or XBP1. Expression of the mitochondrial protective protein BCL-XL or the caspase 8 inhibitor c-FLIP-s, or knock down of death receptor CD95 or the death receptor - caspase 8 linker protein FADD, suppressed killing by [OSU-03012 + PDE5 inhibitor] treatment. CD95 activation was blocked by the nitric oxide synthase inhibitor L-NAME. Knock down of the autophagy regulatory proteins Beclin1 or ATG5 protected cells from OSU-03012 and of [OSU-03012 + PDE5 inhibitor] toxicity. Knock down of IRE1 enhanced OSU-03012 / [OSU-03012 + PDE5 inhibitor] -induced JNK activation and inhibition of JNK suppressed the elevated killing caused by IRE1 knock down. Knock down of CD95 blunted JNK activation. Collectively our data demonstrates that PDE5 inhibitors recruit death receptor signaling to enhance OSU-03012 toxicity in GBM cells.
    Molecular Cancer Therapeutics 08/2014; 13(10). DOI:10.1158/1535-7163.MCT-14-0172 · 5.60 Impact Factor
  • Prithviraj Bose, Steven Grant
    Leukemia Research 08/2014; 38(8). DOI:10.1016/j.leukres.2014.06.007 · 2.69 Impact Factor
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    ABSTRACT: Purpose: To explore the efficacy and define mechanisms of action of co-administration of the PI3K/mTOR inhibitor BEZ235 and pan-HDAC inhibitor panobinostat in DLBCL cells. Experimental Design: Various DLBCL cells were exposed to panobinostat and BEZ235 alone or together after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Genetic strategies defined the functional significance of such changes, and xenograft mouse models were used to assess tumor growth and animal survival. Results: Panobinostat and BEZ235 interacted synergistically in ABC-, GC-, and double-hit DLBCL cells, and MCL cells, but not normal CD34+ cells. Synergism was associated with pronounced AKT dephosphorylation, GSK3 dephosphorylation/activation, Mcl-1 downregulation, Bim up-regulation and increased Bcl-2/Bcl-xL binding, diminished Bax/Bak binding to Bcl-2/Bcl-xL/Mcl-1, increased γH2A.X phosphorylation and histone H3/H4 acetylation, and abrogation of p21CIP1 induction. BEZ235/panobinostat lethality was not susceptible to stromal/microenvironmental forms of resistance. Genetic strategies confirmed significant functional roles for AKT inactivation, Mcl-1 down-regulation, Bim up-regulation, and Bax/Bak in synergism. Finally, co-administration of BEZ235 with panobinostat in immunocompromised mice bearing SU-DHL4-derived tumors significantly reduced tumor growth in association with similar signaling changes observed in vitro, and increased animal survival compared to single agents. Conclusions: BEZ235/panobinostat exhibits potent anti-DLBCL activity, including in poor-prognosis ABC- and double-hit sub-types, but not in normal CD34+ cells. Synergism is most likely multi-factorial, involving AKT inactivation/GSK3 activation, Bim up-regulation, Mcl-1 down-regulation, enhanced DNA damage, and is operative in vivo. Combined PI3K/mTOR and HDAC inhibition warrants further attention in DLBCL.
    Clinical Cancer Research 07/2014; 20(18). DOI:10.1158/1078-0432.CCR-14-0034 · 8.19 Impact Factor
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    ABSTRACT: In selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a time-dependent manner during autophagy, inhibition or knock-down of Cdk9/cyclin T1 transcriptionally down-regulated SQSTM1/p62, but did not affect autophagic flux. These interventions, or shRNA directly targeting SQSTM1/p62, resulted in cargo-loading failure and inefficient autophagy, phenomena recently described in Huntington's disease neurons. These events led to accumulation of the BH3-only protein NBK/Bik on ER membranes, most likely by blocking loading and autophagic degradation of NBK/Bik, culminating in apoptosis. Whereas NBK/Bik up-regulation was further enhanced by disruption of distal autophagic events (e.g., autophagosome maturation) by chloroquine or Lamp2 shRNA, it was substantially diminished by inhibition of autophagy initiation (e.g., genetically by shRNA targeting Ulk1, Beclin-1, or Atg5, or pharmacologically by 3-MA or spautin-1), arguing that NBK/Bik accumulation stems from inefficient autophagy. Finally, NBK/Bik knock-down markedly attenuated apoptosis in vitro and in in vivo. Together, these findings identify novel cross-talk between autophagy and apoptosis, wherein targeting SQSTM1/p62 converts cytoprotective autophagy to an inefficient form due to cargo loading failure, leading to NBK/Bik accumulation which triggers apoptosis.
    Molecular and Cellular Biology 07/2014; 34(18). DOI:10.1128/MCB.01383-13 · 5.04 Impact Factor
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    ABSTRACT: Acute myeloid leukemia continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and anti-apoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mTOR and MEK inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits Bcl-2 and Bcl-xL. Most of these strategies target Mcl-1, an anti-apoptotic protein not inhibited by ABT-737. The PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.
    Physiological Genomics 05/2014; 46(13). DOI:10.1152/physiolgenomics.00173.2013 · 2.81 Impact Factor
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    ABSTRACT: Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro-apoptotic BH3-only proteins Bim and PUMA. Kelch-like ECH-associated protein (Keap)-1 is a BTB/Kelch protein that can regulate the expression of Bcl-2 protein and control apoptotic cell death. Yet, the role of Keap1 in hepatocyte lipotoxicity is unclear. Here we demonstrate that Keap1 protein was rapidly degraded in hepatocytes, through autophagy in a p62-dependent manner, in response to the toxic saturated FFA palmitate, but not following incubation with the non-toxic FFA oleic acid. Stable knockdown of Keap1 expression, using shRNA technology, in hepatocarcinoma cell lines induced spontaneous cell toxicity that was associated with JNK1-dependent upregulation of Bim and PUMA protein levels. Also, Keap1 knockdown further sensitized hepatocytes to lipoapoptosis by palmitate. Likewise, primary hepatocytes isolated from liver-specific Keap1(-/-) mice displayed higher Bim and PUMA protein levels and demonstrated increased sensitivity to palmitate-induced apoptosis than wild-type mouse hepatocytes. Finally, stable knockdown of Bim or PUMA expression prevented cell toxicity induced by loss of Keap1. These results implicate p62-dependent autophagic degradation of Keap1 by palmitate as a mechanism contributing to hepatocyte lipoapoptosis.Cell Death and Differentiation advance online publication, 25 April 2014; doi:10.1038/cdd.2014.49.
    Cell death and differentiation 04/2014; DOI:10.1038/cdd.2014.49 · 8.24 Impact Factor
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    Prithviraj Bose, Yun Dai, Steven Grant
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    ABSTRACT: Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discuss synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.
    Pharmacology [?] Therapeutics 04/2014; 143(3). DOI:10.1016/j.pharmthera.2014.04.004 · 7.75 Impact Factor
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    ABSTRACT: Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of anti-tumor immune responses. Here, we identify clusterin (CLU) as a MDA-7/IL-24 interacting protein in DU-145 cells and investigate the role of MDA-7/IL-24 in regulating CLU expression and mediating the antitumor properties of mda-7/IL-24 in prostate cancer. Ad.mda-7 decreased expression of soluble CLU (sCLU) and increased expression of nuclear CLU (nCLU). In the initial phase of Ad.mda-7 infection sCLU expression increased and CLU interacted with MDA-7/IL-24 producing a cytoprotective effect. Infection of stable clones of DU-145 prostate cancer cells expressing sCLU with Ad.mda-7 resulted in generation of nCLU that correlated with decreased cell viability and increased apoptosis. In the presence of mda-7/IL-24, sCLU-DU-145 cells displayed G(2)/M phase arrest followed by apoptosis. Similarly, Ad.mda-7 infection decreased cell migration by altering cytoskeleton in sCLU-DU-145 cells. Ad.mda-7-treated sCLU-DU-145 cells displayed a significant reduction in tumor growth in mouse xenograft models and reduced angiogenesis when compared to the vector control group. Tumor tissue lysates demonstrated enhanced nCLU generated from sCLU with increased apoptosis in the presence of MDA-7/IL-24. Our findings reveal novel aspects relative to the role of sCLU/nCLU in regulating the anticancer properties of MDA-7/IL-24 that may be exploited for developing enhanced therapies for prostate cancer.
    Journal of Cellular Physiology 04/2014; 227(5):1805-13. DOI:10.1002/jcp.22904 · 3.87 Impact Factor

Publication Stats

16k Citations
2,555.81 Total Impact Points

Institutions

  • 2–2015
    • Virginia Commonwealth University
      • • Division of Hematology/Oncology
      • • Department of Neurosurgery
      • • Department of Biochemistry and Molecular Biology
      • • Massey Cancer Center
      • • School of Medicine
      • • Division of Urology
      • • Department of Radiation Oncology
      • • Department of Pharmacology and Toxicology
      Ричмонд, Virginia, United States
  • 1994–2010
    • Richmond VA Medical Center
      Richmond, Virginia, United States
    • Arizona State University
      • Cancer Research Institute
      Phoenix, Arizona, United States
    • Richmond College
      Richmond, Virginia, United States
  • 2009
    • Loyola University Maryland
      Baltimore, Maryland, United States
    • Mount Sinai School of Medicine
      • Department of Neurosurgery
      Manhattan, New York, United States
  • 1982–2007
    • Columbia University
      • • Department of Urology
      • • Department of Medicine
      • • College of Physicians and Surgeons
      • • Department of Economics
      New York, New York, United States
  • 2003
    • Cornell University
      Итак, New York, United States
    • University of Richmond
      Ричмонд, Virginia, United States
  • 1992–1995
    • Richmond Hospital
      Richmond, British Columbia, Canada
  • 1991–1992
    • Medical University of South Carolina
      • Department of Medicine
      Charleston, SC, United States
  • 1987–1989
    • CUNY Graduate Center
      New York, New York, United States