bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C181: The combination of BKM120, a PI3K inhibitor, with panobinostat synergistically inhibited proliferation and induced apoptosis in lymphoma cells.
Authors: Bodo Juraj , Durkin Lisa , Hill Brian T. , Hsi Eric D. 
Published: June 2012

Abstract
Combination therapies may help to decrease toxicity by allowing use of lower concentrations of individual agents to get a similar biologic effect and/or overcoming clinical resistance to single agent therapy. Recently, we have shown that by the inhibition of PKCβ, a protein kinase increasing survival and proliferation signals, we can shift the balance toward histone deacetylase inhibitor (HDI) induced stress response and the irreversible engagement of the apoptotic cascade in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death of combination of BKM120, a PI3k inhibitor with panobinostat (LBH589), a histone deacetylase inhibitor in B-cell and T-cell lymphoma cell lines.
Flow cytometry assays and PARP cleavage analysis were applied for the study of the apoptosis induction. Cellular protein levels were measured by Western blot. Cytotoxicity of single agents and their combinations was determined by WST-1 proliferation assay. The interaction between BKM120 and panobinostat was examined according to the Chou and Talalay method by using the Calcusyn software.
Combined BKM120/panobinostat treatment synergistically inhibited proliferation and induced apoptosis in tested cell lines. Panobinostat single treatment (concentrations used in combined treatment) induced a slight proliferation inhibition and apoptosis. Interestingly, this treatment increased the level of phosphorylated AKT that might result in an attenuation of further apoptosis. The elevated AKT phosphorylation was significantly diminished by simultaneous treatment with BKM120, which may explain increased induction of apoptosis and inhibition of proliferation in cells treated by BKM120/panobinostat. Moreover, in comparison to the effects of single agent treatments, combined BKM120/panobinostat treatment resulted in significantly lower phospho-RPS6, phospho-GSK3 and p21 protein levels and an increased level of acetylated histone H3.
Our data suggest that PI3k inhibitors in combination with HDI might have potential therapeutic value in lymphoma treatment. The inhibition of PI3k by BKM120 markedly sensitized lymphoma cells to the induction of apoptosis by panobinostat and synergistically inhibited the proliferation of all tested lymphoma cell lines. However, the molecular events underlying the synergistic effect using PI3k inhibitors in combination with HDI remain to be fully elucidated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C181.
Abstract C203: Combined treatment of MK2206 (AKTi) and AZD6224 (MEKi) shows activity in triple-negative breast cancer cell line.
Authors: Soliman Hatem , Noyes David , Cubitt Chris , Lush Richard , Antonia Scott , Sullivan Dan 
Published: June 2012

Abstract
Background: Subsets of triple negative breast cancer (TNBC) such basal have activated signaling through the MAPK-ERK kinase (MEK) pathway. Use of MEK inhibitors in preclinical TNBC models demonstrates some cytostatic activity, but compensatory signaling through the PI3K/AKT pathway diminishes the antitumor effect of MEK inhibitor monotherapy in some TNBC cell lines. Combining a MEK inhibitor with an AKT inhibitor (horizontal blockade) may show increased antitumor activity. We sought to characterize the in vitro effects of the MEK inhibitor AZD6224 combined with the AKT inhibitor MK2206 in three different breast cancer cell lines.
Methods: Cell Titer-Blue cell viability experiments were performed to test dilutions of AZD-6244 or MK-2206 alone or in combination at various molar ratios over a 72 hour time period in MCF-7 (ER+), SKBR3 (HER2+), and MBA-231 (TNBC) cell lines. Synergy was evaluated using Chou and Talalay combination index (CI) analyses (effective dose levels of 0.75, 0.9 and 0.95). Evaluation of MEK and AKT activity in the untreated, AZD6224, MK2206, and AZD+MK treated cells was performed using a BioRad (Hercules, CA) Bio-plex p-ERK1/2 (Thr202/Tyr204, Thr185/Tyr187) + pAKT (Ser473) phosphoprotein assay on a Luminex100.
Results: Synergy was seen only in MDA-231 cells with a mean CI of .492 at a fixed dose ratio of 1:8. The mean fluorescence levels with standard errors of pERK1/2 and pAKT from duplicate experiments are shown in Table 1 in the four treatment groups. The greatest level of baseline MEK activation was seen in the MBA-231 cell line. A significant compensatory increase in p-AKT levels in the MBA-231 cells treated with AZD6224 alone was not observed, but this was seen in the SKBR3 cells.
Conclusions: The combination of AZD6224+MK2206 demonstrates enhanced antitumor activity in the TNBC MBA-231 cell line over AZD6224 monotherapy. The strategy of combining a MEK inhibitor with an AKT inhibitor should be further explored in the treatment of TNBC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C203.
Abstract C204: Potentiation of the novel topoisomerase I inhibitor indenoisoquinoline LMP-400 by the Chk1/2 inhibitor, AZD7762.
Authors: Aris Sheena M. , Pommier Yves G. 
Published: June 2012

Abstract
Novel topoisomerase I (Top1) inhibitors are in clinical development to circumvent the drawbacks of camptothecins (1–3). Here we report molecular investigations of the clinical indenoisoquinoline Top1 inhibitor, LMP-400 by itself and in combination with the cell cycle checkpoint inhibitor, AZD7762 (4). Drug effects on DNA replication and killing of cancer cells were examined. LMP-400 shows synergistic antiproliferative activity when combined with AZD7762 in human colon carcinoma HT-29 and HCT-15 cells. Inhibition of S-phase progression and bromodeoxyuridine incorporation was similarly induced by LMP-400 and CPT and was abrogated by AZD7762. Replication studied by single DNA molecule analyses and immunofluorescence microscopy (molecular combing) (5) showed rapid inhibition of fork progression in response to LMP-400 treatment with subsequent recapitulation after AZD7762 addition. Consistent with cell cycle checkpoint abrogation, AZD7762 inhibited both the activation of Chk1 and Chk2 autophosphorylations in LMP-400-treated cells. In spite of the potent dual inhibition of Chk1 and Chk2 at nanomolar concentrations of AZD7762, cell cycle inhibition and synergism with LMP-400 were only observed at higher concentrations and independently of Chk2 both in Chk2-complemented HT-15 and Chk2 knockout HCT-116 cells. Our study demonstrates the rationale for combining checkpoint kinase inhibitors and the novel non-camptothecin indenoisoquinoline inhibitors.
References:
1. Pommier Y, Cushman M. The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives. Mol Cancer Ther 2009; 8: 1008–14.
2. Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 2010; 17: 421–33.
3. Teicher BA. Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochem Pharmacol 2008; 75: 1262–71.
4. McNeely S, Conti C, Sheikh T, et al. Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase. Cell Cycle 2010; 9: 995–1004.
5. Conti C, Seiler J, Pommier Y. The Mammalian DNA Replication Elongation Checkpoint: Implication of Chk1 and Relationship with Origin Firing as Determined by Single DNA Molecule and Single Cell Analyses. Cell Cycle 2007; 6: 2760–7.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C204.
Abstract C225: Differential regulation of simultaneous antitumor and alloreactive CD8+ T cell responses in the same host by rapamycin.
Authors: Vareki Saman Maleki , Harding Martha , Waithman Jason , Zanker Damien , Shivji Adil , Rytelewski Mateusz , Mazzuca Delfina , Yekta Maryam , Chen Weisan , Schell Todd , Haeryfar S.M. Mansour 
Published: June 2012

Abstract
Rapamycin is an immunosuppressive agent routinely used in organ transplantation, but also paradoxically, exerts antiviral and anti-tumor activities. Pathogen-specific memory CD8+ T cell (TCD8) responses were recently found to be augmented by rapamycin. However, whether rapamycin influences the magnitude and quality of anticancer TCD8 responses is unknown. Importantly, how rapamycin may regulate simultaneous virus/tumor-specific and alloreactive TCD8 in the same host remains unexplored. To answer these questions, we primed wild-type mice with allogeneic cells concomitantly expressing simian virus 40 large tumor antigen (T Ag), a viral oncoprotein with well-defined epitopes. Rapamycin selectively improved the cross-priming of TCD8 specific for T Ag's most immunodominant epitope called site IV. Rapamycin-treated mice also had a high percentage of splenic CD127highKLRG1low TCD8 as well as an increased frequency of site IV-specific T cells long after the peak of their primary response. When site IV was presented as a cytosolic minigene encoded by a recombinant vaccinia virus, rapamycin failed to enhance the site IV-specific response. Therefore, the nature and presentation mode of antigen determine the susceptibility to the adjuvant effect of rapamycin. Our findings reveal the unexpected benefit of rapamycin treatment in recipients of allografts co-expressing tumor/viral Ags.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C225.
Abstract C227: Blockade of tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor overcomes tumor recurrence after radiation therapy.
Authors: Xu Jingying , Escamilla Jemima , McBride William , Wu Lily 
Published: June 2012

Abstract
Radiotherapy is one of the major frontline treatments for prostate cancer (PCa). However, a large proportion of patients suffer from tumor recurrence after radiotherapy. Tumor-infiltrating myeloid cells (TIMs), including CD11b+F4/80+ tumor-associated macrophages (TAM) and CD11b+Gr-1+ myeloid-derived suppressive cells (MDSCs), play critical roles in promoting tumoral angiogenesis, tissue remodeling and immunosuppression. Recently several reports suggested that TIMs might play a critical role in mediating tumor regrowth after radiation therapy. Here, we showed that there is enhanced recruitment of both TAMs and MDSCs after 5 days of 3 Gy radiation treatment in subcutaneously implanted RM-1 syngeneic PCa model. Infiltration of two MDSC subsets, CD11b+Gr-1loLy6Chi mononuclear-MDSC (MO-MDSC) and CD11b+Gr-1hiLy6Clo polymorphnuclear-MDSC (PMN-MDSC), are both increased. Although treatment is localized to the tumor site, the effects of radiation are systematic. Dramatic increases of MDSCs and TAMs were also observed in the spleen, lymph nodes and peripheral blood. To better understand the mechanism of enhanced recruitment of myeloid cells to tumors, we performed RT-PCR analysis on tumor tissues for commonly known factors that mediate the recruitment of myeloid cells. Indeed, we found that macrophage colony stimulating factor 1 (M-CSF-1 or CSF-1) increases by 2 fold in irradiated tumors compared to non-irradiated tumors. In vitro migration assays using conditioned medium from irradiated tumor cells increases migration of RAW246.7 macrophages by 4 fold, and this increase is completely blocked by the very selective CSF1R inhibitor, GW2580.
Immunohistochemical analysis confirmed the induction of TAMs and MDSC recruitment to tumors, and the effectiveness of GW2580 in blocking their infiltration. Most importantly, combination therapy using GW2580 with radiation synergistically suppressed tumor growth and recurrence. This data highlights the importance of CSF1/CSF1R signaling in the recruitment of TIMs post-radiation treatment and their significant role in promoting tumor re-growth. Moreover, our data could potentially provide a more effective and durable treatment strategy for PCa patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C227.
Abstract C239: Progesterone receptor B through Sp1 induces the phosphatase and tensin homologue deleted from chromosome 10 (PTEN) gene promoter activity and cell death in breast cancer cell lines.
Authors: de Amicis Francesca , Guido Carmela , Santoro Marta , Avena Paola , Panza Salvatore , And Sebastiano , Aquila Saveria 
Published: June 2012

Abstract
Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor attracting considerable attention as new target for effective therapeutic strategies in breast cancer. While recent studies suggest the down-regulation of PTEN by Estrogen Receptor alpha, the role of Progesterone Receptor (PR) is not clearly established.
In the present study we report that PR produces a significant inhibition of MCF-7 breast cancer cell survival with a concomitant increase of PTEN protein, mRNA and gene promoter activity. On the contrary PRs failed to enhance the transcriptional activity of the PTEN promoter lacking the region between −1398 bp to −1118 bp. By analyzing this DNA sequence to search potential binding sites for transcription factors, we observed that this region contains several DNA motifs known to bind the transcription factors Sp1that has been shown to interact with PRs, activating specific gene transcription. In our experimental conditions mithramycin, prevented the PTEN promoter transactivation on OHPg treatment. ChIP analyses showed specific recruitment of PR, Sp1 and RNA polymerase II upon progesterone treatment at PTEN promoter. The persistence of such effects in T47 cells which express high PR levels, addresses how PR/PTEN signalling may be considered as useful pharmacological tool to be exploited for innovative adjuvant strategies in breast cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C239.
Abstract C31: Derivatives of 3a-aza-cyclopenta[a]indene effectively suppress the growth of P-glycoprotein overexpressing cells in in vitro and in vivo systems.
Authors: Lee Te-Chang , Lee Pei-Chih , Kakadiya Rajesh , Su Tsann-Long 
Published: June 2012

Abstract
We synthesized several novel bifunctional alkylating derivatives of 3a-aza-cyclopenta[a]indene (BO-1012, BO-1005, BO-1099, and BO-1101), which are potent DNA interstrand crosslinking agents. In in vitro cytotoxicity assay, these compounds were more cytotoxic to multidrug resistant (MDR) cells, such as KBvin10, KBtax50, and CEM/VBL, than their parental cells. Using a xenograft model, BO-1012, at a dose of 5 mg/kg, partially suppressed the growth of parental KB cells but completely suppressed the growth of KBvin10 cells in nude mice. In exploring the possible mechanism, we found that DNA double-strand break (DSB) repair activity in MDR cells, KBvin10 and CEM/VBL, was significantly reduced compared to their parental cells, KB and CEM. Reduced DSB repair activity in KBvin10 cells was likely due to a defect in nuclear translocation of DNA-PK, a component of the non-homologous end-joining repair machinery. Furthermore, BO-1012-induced DNA-PK translocation from the cytosol into the nucleus in KB cells is associated with activation of the Src/nuclear EGFR cascade, which is defective in MDR cells. Since knockdown of P-glycoprotein (P-gp) by siRNA reactivated the Src/nuclear EGFR cascade, DNA-PK translocation, and DNA repair activity in MDR cells, overexpression of P-gp attenuates the activity of DNA DSB repair via suppression of SRc/nuclear EGFR cascade. Therefore, DNA interstrand crosslinking agents may have potential therapeutic use against P-gp-overexpressing MDR cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C31.
Abstract C36: Hypoxia or glutathione depletion increase apoptotic response to PRIMA-1 in p53-mutated and nonmutated human breast cancer cells.
Authors: Rieber Manuel , Rieber Mary Strasberg 
Published: June 2012

Abstract
Background: Hypoxia, dysfunction of the p53 tumor suppressor gene product, and intracellular glutathione levels are important in modulating resistance of solid tumors to chemotherapy. PRIMA-1 (bis(hydroxymethyl-3-quinuclidinone) and its structural analog PRIMA-1met are used to reactivate mutant p53 and induce tumor cell apoptosis. However, PRIMA-1met as a single agent was reportedly ineffective in lowering clonogenic survival of (mut p53) DU145 prostate cancer cells, under hypoxia.
Purpose: Here, we investigated whether the toxicity of PRIMA-1 (p53 reactivation and induction of massive apoptosis) is influenced by hypoxia in matched human breast cancer cells with unequal p53 genotype, and by agents that decrease glutathione levels in matched wt p53 human breast cancer cells with different Mn-SOD expression.
Methodology: Cell survival was assessed by cytofluorometric and clonogenic analysis, estimating apoptosis-associated PARP cleavage by Western blot.
Results: Mutant p53 breast cancer cells were susceptible to PRIMA-1 under normoxia and this response increased under hypoxia. Matched wt p53 breast carcinoma cells were resistant to comparable PRIMA-1 concentrations in normoxia but became sensitive to it under hypoxia. In contrast, hypoxia did not enhance cytotoxicity of nutlin-3a, known to increase wt p53 signaling by inhibit MDM2 binding to p53. Normoxic resistance to PRIMA-1 in wt p53 breast cancer cells was also antagonized by glutathione depletion or Mn-SOD over-expression.
Conclusions: Hypoxia, a common feature of the microenvironment of solid tumors is believed to promote cancer progression and poor clinical outcome. This report is the first to show that hypoxia enhances PRIMA-1 toxicity against human breast cancer cells with mutated or non-mutated TP53 status. We propose that PRIMA-1 may help to counteract hypoxia-acquired resistance to cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C36.
Abstract C70: Antitumor activity of CUDC-907, a single small molecule inhibitor that targets both PI3K and HDAC, in hematologic cancer models.
Authors: Bao Rudi , Wang Dagong , Qu Hui , Wang Jing , Atoyan Ruzanna , Xu Guang-Xin , Yin Ling , Zifcak Brian , Borek Mylissa , Samson Maria , Ma Anna , DellaRocca Steven , Zhai Hai-Xiao , Lai Cheng-Jung , Pepicelli Carmen , Cai Xiong , Qian Changgeng 
Published: June 2012

Abstract
In order to achieve cancer signaling network disruption and overcome primary and/or secondary resistance to standard of care agents in hematologic cancers, we have developed a novel class of dual HDAC and PI3K inhibitors by integrating a HDAC inhibitory functionality into a pharmacophore of PI3K inhibitors. Utilizing structure-based design and extensive SAR approach, CUDC-907 has been selected as a clinical candidate that inhibits not only PI3K directly but also other essential signaling pathways indirectly through epigenetic regulation following HDAC inhibition. Enzymatic assays indicate that CUDC-907 potently inhibits Class I PI3K subtypes as well as Class I and II HDAC subtypes. In anti-proliferation assays, CUDC-907 displays potent inhibition of proliferation of a variety of hematologic cancer cells (mean IC50 = 27nM in 23 cell lines). In mechanism studies, CUDC-907 potently and durably inhibits HDAC and PI3K, as indicated by increase of acetylated histone H3, inhibition of phospho-AKT and phospho-STAT3, decrease of anti-apoptotic molecules (BCL-2, survivin, etc.), and induction of P21, acetylated P53 and cleaved caspase3. CUDC-907 is orally bioavailable in animals, and displays a favorable PK profile in tumor-bearing animals. PD studies in xenograft models exhibit that CUDC-907 dose-dependently inhibits both targets, decreases tumor cell proliferation, and induces apoptosis in hematologic tumor xenografts, correlating well with its drug exposure in tumors. In efficacy studies, CUDC-907 inhibits growth of subcutaneously implanted tumor xenografts of hematologic cancers in a dose-dependent manner. Furthermore, in a Daudi NHL model, CUDC-907 is more efficacious than either a single PI3K or HDAC inhibitor reference compound or a combination of the two single agents at maximally tolerated doses. CUDC-907 also displays a favorable safety profiles. Taken together, CUDC-907 may offer greater therapeutic benefits through broad network disruption in hematologic cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C70.