bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2622: CIP2A mediates the apoptotic effect of bortezomib on triple negative breast cancer cells
Authors: Tseng Ling-Min , Liu Chun-Yu , Chang Kung-Chi , Shiau Chung-Wai , Cheng Ann-Lii , Kuo Hsin-Yu , Tzeng Cheng-Hwai , Chen Kuen-Feng 
Published: June 2012

Abstract
Background: Triple negative breast cancer (TNBC) is with aggressive behaviors and poor prognosis because of the absence of a specific target for the tumor, such as in endocrine therapy and anti-HER2 therapy. Bortezomib, a proteasome inhibitor, may exert potential efficacy in TNBC through its multiple cellular effects. Our previous study has shown that CIP2A, cancerous inhibitor of PP2A, mediates effects of bortezomib on phospho-Akt (P-Akt) and apoptosis in hepatocellular carcinoma. (Oncogene, 2010). Here, we tested efficacy of bortezomib to TNBC and examined the drug mechanism. Methods: Triple negative breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Results: Bortezomib induced apoptosis in association with down-regulation of CIP2A and P-Akt in a dose- and time-dependent manner in three TNBC cells lines (HCC-1937, MDA MB-468, MDA MB-231) but not in hormone positive MCF-7 cells. Over-expression of CIP2A in MDA MB-231 cells protected cells from bortezomib-induced apoptosis, and down-regulation of CIP2A by siRNA overcame the apoptotic resistance to bortezomib in MCF-7 cells. These data indicate that inhibiton of CIP2A determined the sensitivity of bortezomib to breast cancer cells. Importantly, bortezomib showed in vivo efficacy in HCC-1937 xenografted tumor. Conclusions: CIP2A mediates bortezomib-induced apoptosis in TNBC. Targeting CIP2A-PP2A-P-Akt signaling pathway is a novel approach for the treatment of TNBC. Supported by VGHTPE 100DHA0100591 and V99C1-059.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2622. doi:10.1158/1538-7445.AM2011-2622
Abstract 2625: MGCD0103, an oral isotype-selective HDAC inhibitor, has antitumor activity via the induction of the expression of Annexin A1 on AML1/ETO AML in vitro and in vivo
Authors: Nameki Daisuke , Masuko Norio , Fujita Ryouto , Sugiura Shin , Yamamoto Yasuji , Minamiguchi Kazuhisa , Matsuo Ken-Ichi 
Published: June 2012

Abstract
MGCD0103 is a non-hydroxamate and an orally available isotype-selective HDAC inhibitor (HDACi) whose clinical activity has been shown in multiple phase II trials in patients with relapsed or refractory Hodgkin lymphoma, high-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). It has previously been shown that FK-228, class I selective HDACi, and SAHA, isotype-nonselective HDACi, activate apoptosis through induction of pro-apoptotic protein annexin A1 on t(8;21) translocated AML cells which produce AML1-ETO fusion protein (AML1/ETO AML). To determine whether the existence of t(8;21) translocation in AML affect on the efficacy of MGCD0103, we explored the action of MGCD0103 on anti-tumor activity in AML1/ETO AML and AML1/ETO-negative AML xenograft models in mice in vivo and investigated the putative mechanism of the efficacy.MGCD0103 was orally administrated to the NOD SCID mice implanted with AML1/ETO AML xenograft or AML1/ETO-negative AML xenograft using an intermittent dosing regimen (3 times a week) for 3 weeks. Tumor volume was calculated during the treatment and tumor weight at final date was measured for final evaluation. In addition, we measured not only the activity of apoptosis related factor, caspase-3/7, but also the expression of pro-apoptotic protein annexin A1 that induced by MGCD0103 in vitro and in vivo. Further understanding of the mechanism of MGCD0103, we assessed the acetylated histone in the promoter region of annexin A1 using ChIP assay in vitro whether its induction is derived from the histone acetylation activity of MGCD0103. MGCD0103 showed a strong growth inhibition of the tumor in the AML1/ETO AML xenograft. There were significant decreases in the AML1/ETO AML tumor volume and weight in the MGCD0103 treated group compared with the control group, but not in the AML1/ETO-negative AML xenograft. Caspase-3/7 was strongly activated and the expression of annexin A1 was significantly induced in the MGCD0103 treated AML1/ETO AML cells. In addition, histone of annexin A1 promoter region in AML1/ETO AML tended to be acetylated more than the AML1/ETO-negative AML cells by MGCD0103. These data possibly indicate that the strong anti-tumor effect was derived from the direct effect of MGCD0103 that leads apoptosis of the AML1/ETO AML cells through the induction of acetylation of annexin A1 promoter. Selection of AML patients with t(8;21) translocation may leads good therapeutic outcome of MGCD0103 in AML treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2011-2625
Abstract 2628: Antitumor activity of MPC-3100, a synthetic Hsp90 inhibitor, in combination with erlotinib and sorafenib
Authors: Baichwal Vijay R. , Brown Brita , Wettstein Daniel , Papac Damon I. , Mather Gary G. , Carlson Robert O. 
Published: June 2012

Abstract
Introduction: MPC-3100 is a fully synthetic, orally bioavailable, Hsp90 inhibitor in clinical development. It is active as a single agent in xenograft models with many cancer types including colon, gastric, ovary, prostate, breast, lung and myeloid leukemia. We evaluate here the activity of MPC-3100 in combination with erlotinib or sorafenib in xenograft models.
Methods: Three to five million cells, depending on cell-type, were implanted subcutaneously into athymic mice (nu/nu) for tumor studies. Dosing was initiated when median tumor volume was &gt;100 mm3. All compounds were dosed orally, once daily. MPC-3100 (100 mg/kg) and erlotinib (100 mg/kg) were dosed on Days 1-21 and sorafenib (60 mg/kg) was dosed on Days 1-9.
Results: Anti-tumor activity for the combination of MPC-3100 and erlotinib was compared to that of the single agents in a lung cancer (A549) xenograft model sensitive to EGFR inhibition. Administration of MPC-3100 or erlotinib resulted in 52% and 64% tumor growth inhibition (TGI), respectively relative to vehicle by the end of dosing on Day 19. By contrast, the combination of MPC-3100 and erlotinib resulted in 30% tumor regression over the same period. Thus the combination of MPC-3100 and erlotinib was more effective at inhibiting tumor growth than either agent alone (p&lt;0.05). The combined anti-tumor activity of MPC-3100 and sorafenib was compared to administration of the single agents in a xenograft model with the melanoma cell line A375 that harbors the activating B-raf mutation, V600E. The median tumor volume (MTV) of the cohorts dosed with vehicle, MPC-3100 or sorafenib as single agents was comparable and increased by 4.8-, 6.4- and 8.2-fold, respectively by the end of dosing on study Day 20, whereas MTV of the cohort dosed with a combination of MPC-3100 and sorafenib increased by only 1.6-fold. The combination of MPC-3100 and sorafenib resulted in 66% tumor growth inhibition relative to vehicle on Day 20 and was more effective at inhibiting tumor growth than single agent (p&lt;0.05).
Conclusions: The combination of MPC-3100 with erlotinib or sorafenib shows greater anti-tumor activity than either agent alone. Thus, in addition to its broad activity in xenograft models as a single agent, MPC-3100 has the potential to be combined with other targeted therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2628. doi:10.1158/1538-7445.AM2011-2628
Abstract 2632: SAHA loosens chromatin structure and increases DNA damage in human lung cancer cells induced by arsenic trioxide
Authors: Chien Chia-Wen , Yao Ju-Hsien , Chang Shih-Yu , Lee Pei-Chih , Lee Te-Chang 
Published: June 2012

Abstract
The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well-documented. ATO may cause DNA damage through the generation of reactive oxygen intermediates. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), modulates gene or protein expression via histone dependent or independent pathway that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. The objective of this study is to investigate whether ATO and SAHA could synergistically enhanced cell killing to cancer cells. The present studies showed that combined treatment with ATO and SAHA results in enhanced suppression of non-small cell lung carcinoma (NSCLC) H1299 cells in vitro and in xenograft mouse model. By analyzing the annexin V positive cells, apoptotic cell death is significantly enhanced in combined treatment. At the doses used, ATO does not interfere with the cell cycle progression, whereas SAHA induces the expression of p21WAF1/CIP1 and leads to G1 arrest. By the aid of Comet assay, we demonstrated that ATO induces DNA breaks in H1299 cells, but not SAHA. However, co-treatment with SAHA and ATO significantly increases ATO-induced DNA damage. Moreover, SAHA enhances acetylation of histone H3 and sensitize genomic DNA to DNase I digestion. Our present results suggest that SAHA may result in chromatin relaxation, and lead to cells become more susceptible to ATO for causing DNA damage. Therefore, combination of SAHA with ATO may provide effective approach to treatment of lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2632. doi:10.1158/1538-7445.AM2011-2632
Abstract 2635: CBP501-calmodulin binding contributes to sensitizing tumor cells to CDDP and BLM
Authors: MINE NAOKI , Yamamoto Sayaka , Saito Naoya , Kufe Donald W. , VonHoff Daniel D. , Kawabe Takumi 
Published: June 2012

Abstract
CBP501 is an anti-cancer drug candidate currently under the Phase II clinical trials on non-small cell lung carcinoma (NSCLC) and malignant pleural mesotherioma (MPM). CBP501 was originally described as a unique G2 checkpoint-directed agent that binds to 14-3-3, inhibiting the actions of Chk1, Chk2, MAPKAP-K2, or C-Tak1. However, unlike a G2 checkpoint inhibitor, CBP501 clearly enhances the G2/M accumulation induced by cisplatin (CDDP) or bleomycin (BLM) at low dose and short exposure to tumor cells. It does not affect the accumulation at G2/M by radiation, doxorubicin or 5-FU treatment in the same condition. Our recent findings point to an additional mechanis of action (MOA) for CBP501.
The enhanced G2/M accumulation by CDDP results from increased intracellular platinum concentration, which leads to increased binding of platinum to DNA. The observed CBP501-induced platinum accumulation is negated in the presence of excess Ca2+. Some calmodulin (CaM) inhibitors behave similarly to CBP501. But the therapeutic window of CBP501 was broader than CaM inhibitors. Furthermore, analysis by surface plasmon resonance (SPR) reveals a direct, high-affinity molecular interaction between CBP501 and CaM (Kd=4.62×10−8M) that is reversed by Ca2+, whereas the Kd for the complex between CBP501 and 14-3-3 is some 10-fold weaker and is Ca2+-independent. We conclude that calmodulin inhibition plays important role in the activity of CBP501 in sensitizing cancer cells to CDDP or BLM. This report presents the prospects for the development of a new class of anti-cancer drugs through the addition of unique calmodulin inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2635. doi:10.1158/1538-7445.AM2011-2635
Abstract 2645: PEITC induces cell death in melanoma cells through redox mechanisms
Authors: Ahmed Kausar Begam Riaz , Feng Li , Huang Peng 
Published: June 2012

Abstract
Melanoma is one of the deadliest types of cancers accounting for about 80% of skin cancer deaths. Reactive oxygen species (ROS), produced by the mitochondrial respiratory chain and other biochemical mechanisms, play a critical role in melanoma progression through activation of transcription factors AP-1 and NF- κB and loss of E-cadherin. However, a further elevated level of ROS in cells, beyond a certain cellular threshold, may lead to mitochondrial damage, cytotoxicity and subsequent cell death. Hence, increasing ROS levels by either activating a ROS-generating enzyme or by depletion of antioxidants is a plausible strategy to induce cell killing in melanoma cells. The natural compound β-phenylethyl isothiocyanate (PEITC) found in cruciferous vegetables exhibits significant antitumor activity. Recent studies demonstrated that PEITC selectively induced cancer cell death by disabling the glutathione antioxidant system. Based on these observations, we hypothesize that PEITC may preferentially eliminate melanoma cells through ROS-mediated mechanism due to the increased basal ROS levels in melanoma cells and their high dependence on glutathione. To test this hypothesis, the cytotoxic effect of PEITC was tested in a panel of melanoma cell lines in comparison with normal melanocytes. Our results demonstrated that PEITC had time- and concentration-dependent antiproliferative effect in melanoma cells. The inhibitory effect is melanoma specific, since PEITC had minimum cytotoxic activity in normal melanocytes. Further analysis of ROS by FACS using the fluorescent dye DCFDA revealed that this cell death was primarily due to increased ROS accumulation triggered by PEITC-induced depletion of cellular glutathione. This aberrant increase in ROS caused mitochondrial membrane damage, as determined by biochemical analysis using Rhodamine 123, and subsequent cell death through apoptosis. Importantly, PEITC was very effective in melanoma cells, which exhibited resistance to standard anti-tumor drugs like temozolomide (TMZ) and carmustine (BCNU). Our study suggests that PEITC may be an effective anti-melanoma therapeutic agent that warrants further pre-clinical and clinical investigation. Our work is now directed towards identifying other ROS related cellular mechanisms that can be exploited to increase the therapeutic specificity and sensitivity of PEITC in melanoma cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2011-2645
Abstract 2651: Cucurbitacin I (JSI-124) activates the JNK signaling pathway leading to transcriptional up-regulation of vascular endothelial growth factor in B leukemia cells
Authors: Ishdorj Ganchimeg , Johnston James B. , Gibson Spence B. 
Published: June 2012

Abstract
JSI-124 (Cucurbitain I) is a biochemical compound isolated from the herbal plant families, which have been used as folk medicines for centuries in Asian countries. The molecular mechanisms for this inhibitor acts primarily through STAT3 inhibition in many tumors, including chronic lymphocytic leukemia. However, other molecular targets of JSI-124 are not fully understood. The objective of this study was to determine the molecular targets of JSI-124 beyond STAT3. Chemotherapeutic drugs often induce a stress response in cancer cells. One of early stress response pathways is the c-Jun N-terminal kinase (JNK) pathway. Herein, we show that JSI-124 activates JNK and increased the expression of c-Jun protein in the B leukemia cell lines BJAB, I-83 and NALM-6. Interestingly, the inhibition of the JNK signaling pathway failed to effect JSI-124 induced cell cycle arrest or apoptosis in these leukemia cells but repressed c-Jun level. Furthermore, JNK activation also failed to effect JSI-124 inhibition of STAT3 phosphorylation in these cells. It is known that one of the important factors involved in JNK signaling is Vascular Endothelial Growth Factor (VEGF). We found that JSI-124 treated BJAB cells showed an increased in mRNA and protein level in VEGF in BJAB, I-83 and NALM-6 cells. Knockdown of c-Jun expression and inhibition of JNK activation significantly blocked JSI-124 induced VEGF expression. Taken together, our data demonstrate that JSI-124 activates JNK signaling pathway leading to VEGF expression independent of inhibition of STAT3 activation. This could lead to increased angiogenesis in B leukemia cells treated with JSI-124.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2651. doi:10.1158/1538-7445.AM2011-2651
Abstract 2653: Nelfinavir induces apoptosis in hormone-resistant prostate cancer cells through inhibition of regulated intramembrane proteolysis of SREBP-1 and ATF6
Authors: Guan Min 
Published: June 2012

Abstract
We previously reported that nelfinavir-induced apoptosis in liposarcoma is a direct result of regulated intramembrane proteolysis (RIP) inhibition mediated through inhibition of site-2 protease (S2P) activity. We now report similar effects in hormone-resistant prostate cancer (HR-PC) cells. Nelfinavir-mediated RIP inhibition leads to accumulation of unprocessed sterol regulatory element binding protein-1 (SREBP-1) and activating transcription factor 6 (ATF6). This results in endoplasmic reticulum (ER) stress and inhibition of the unfolded protein response (UPR), which leads to autophagy and caspase activation. Confocal microscopy and proliferation studies demonstrate that nelfinavir inhibits the nuclear translocation of SREBP-1-EGFP and ATF6-EGFP fusion proteins, and reduces PC proliferation, similar to the situation observed in site-1 protease (S1P) and S2P-siRNA knockdown cells. Western blotting in nelfinavir and S1P and/or S2P-siRNA knockdown cells confirms accumulation of precursor SREBP-1 and ATF6. Treatment of PC cells with DCI, an S1P inhibitor did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduces the molecular and biological phenotype observed in nelfinavir-treated HR-PC cells. These results are consistent with the hypothesis that S2P is a target of nelfinavir. These findings, together with our previous report, provide new insight into the mechanism of nelfinavir-mediated induction of ER stress and cell death in cancer, and are the first to report targeting S2P therapeutically for cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2653. doi:10.1158/1538-7445.AM2011-2653
Abstract 267: E2F1 regulates human TRAIL promoter and mediates Interferon alpha 2a response
Authors: Kunigal Sateesh S. , Joshi Bharat , Chellappan Srikumar S. 
Published: June 2012

Abstract
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2L) is a member of the TNF gene superfamily that induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it selectively induces apoptosis in many transformed cells and has been explored as an anti-cancer agent. Earlier studies have shown the upstream region of human TRAIL gene, contain NFAT, AP-1, and Sp1 binding sites which have been shown to regulate expression of multiple cytokines, but the transcriptional regulation of TRAIL has not yet been elucidated in detail. An examination of the human TRAIL promoter showed the presence of five binding sites for the E2F transcription factors. E2F1 is a transcription factor that plays a well-documented role in cell cycle regulation, differentiation and senescence. In addition to its proliferative effects, E2F1 has been shown to have potent apoptotic properties as well, under appropriate conditions. E2F1 can induce apoptosis via several p53-dependent or -independent mechanisms, either through direct transactivation of proapoptotic genes such as p73, apaf-1 (apoptosis protease-activating factor 1) and caspases or transcriptional repression. Studies presented here show that the human TRAIL promoter is E2F responsive in multiple lung cancer cell lines. Chromatin immunoprecipitation assays showed the recruitment of E2F1 as well as Rb to the TRAIL promoter and transient transfection of E2F1 could induce the expression of a TRAIL-luciferase reporter construct. TRAIL could be repressed by Rb, but this repression could be overcome by the transient transfection of ASK-1, Raf-1 or p38 kinases as well as cycling D or E, suggesting that this promoter is responsive to extracellular signals that can regulate Rb function. It has been shown that stimulation of natural killer cells by Interferon alpha-2a leads to upregulated TRAIL expression. We find that Interferon alpha 2a (IFN α 2a) stimulated lung cancer cell lines exhibited high TRAIL luciferase activity and depletion of E2F1 by siRNA techniques prevented the induction of TRAIL. These results suggest that E2F1 as a critical regulator of TRAIL expression and might facilitate death-receptor-mediated apoptosis. These observations raise the possibility that E2F-mediated regulation of TRAIL might have effects on the immune response of lung cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 267. doi:10.1158/1538-7445.AM2011-267