bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 810: O6 methylguanine DNA methyltransferase inhibition sensitizes pancreatic cancer cells to temozolomide
Authors: Bobustuc George C. , Ticku Jonathan , Patel Anand , Srivenugopal Kalkunte S. , Konduri Santhi D. 
Published: May 2015

Abstract
O6 methylguanine DNA methyltransferease (MGMT) is overexpressed in majority of cancers including pancreatic cancer. MGMT has been the focus of significant research for its role in the repair of DNA damage caused by alkylating agents. In the present study, we tested the administration of the MGMT inhibitor O6-benzylguanine (BG) at non-toxic doses in combination with an alkylator TMZ (temozolomide) on pancreatic cancer cells (L3.6 pl and PANC1) in cell culture and xenograft model. Here, we report that TMZ decreases pancreatic cancer cell growth in a dose dependent manner. BG further sensitizes pancreatic cancer cells to TMZ and significantly inhibits pancreatic cancer growth. We also report that BG, either alone or in combination with TMZ, inhibits the expression of MGMT, Ki-67 and BIRC5 (survivin), which are involved in pancreatic tumorigenesis and cell division, and induces the expression of p21cip1 cell cycle inhibitor. Microarray analysis revealed that BG significantly decreased the transcription of a group of proto-oncogenes, growth factors, cell cycle and overall transcription regulators involved in tumorigenesis like ARHGDIB, IGFL1, KIF20A, CA9, MMP10 and E2F2 and increased the transcription of a variety of genes involved in tissue differentiation, cell cycle regulation and invasion inhibitors like GDF15, CDKN1A and TIMP1. In our pancreatic cancer xenograft model, BG +/- TMZ significantly inhibited pancreatic tumor growth in vivo compared to single agent TMZ or controls. Further, BG promotes p53 function leading to growth inhibition, in part substantiating the underlying mechanism of BIRC5 (survivin) inhibition and p21cip1 induction. In conclusion, our findings suggest that MGMT inhibition may potentially provide a novel therapeutic approach in pancreatic cancer by opening the option of using (oral) alkylators like TMZ.
Citation Format: George C. Bobustuc, Jonathan Ticku, Anand Patel, Kalkunte S. Srivenugopal, Santhi D. Konduri. O6 methylguanine DNA methyltransferase inhibition sensitizes pancreatic cancer cells to temozolomide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 810. doi:10.1158/1538-7445.AM2014-810
Abstract 814: Novel aspirin based selenium compounds as therapy against pancreatic cancer
Authors: Karelia Deepkamal N. , Pandey Manoj K. , Plano Daniel , Amin Shantu , Sharma Arun K. 
Published: May 2015

Abstract
Inflammation plays an important role in tumor growth promotion and has been linked to several human cancers. Evidences have demonstrated that inflammation has a high correlation with pancreatic cancer (PC) growth and promotion. An important mediator of inflammatory process is Cyclooxygenase 2 (COX-2) protein, which has been shown to be over-expressed in PC. Another major pathway which is crucial for inflammatory responses, cell proliferation, and resistance to apoptosis is the nuclear factor κB (NF-κB) pathway. It has been demonstrated that NF-κB pathway is responsible for drug resistance in PC. Aspirin, a well-known non-steroidal anti-inflammatory drug (NSAID), has been shown to have anti-cancer effects against PC. The mechanism of action of aspirin against PC is partially dependent on COX inhibition, as well as COX independent mechanism. Through extensive structure-activity relationship studies on Se-NSAID compounds, we have recently identified two Se-Aspirin compounds, ASD-43 and ASD-49, designed by incorporating selenium (Se) into salicylic acid structure, rendering it lethal to cancer cells. Previously, we had reported that Se-aspirin hybrid compounds were effective in different cancers, including PC. In this study we sought to evaluate the mechanism of action of these compounds in inhibiting the growth of PC. Since aspirin induces its effect partially by inhibiting COX, we hypothesized that these agents (ASD-43 and ASD-49) showed their anti-cancer activity by potently inhibiting COX activity as well as by modulating the inflammatory NF-κB pathway. Our studies, in Panc-1 cells, have shown that both ASD-43 and ASD-49 inhibited the degradation of IκB-alpha, which inhibits NF-κB from going into the nucleus, in presence of tumor necrosis factor (TNF). Upon treatment with ASD-43 and ASD-49, NF-κB regulated proteins like survivin and Bcl-xL expression was down regulated. Furthermore, a dose dependent induction of apoptosis in these cells was detected by activation of caspase-3 and PARP cleavage. Taken together, these results suggest that both ASD-43 and ASD-49 may represent potentially promising therapeutic agents for PC that induce apoptosis via the inhibition of COX and NF-κB pathways. Detailed investigations regarding the efficacy and mechanism of action of these compounds will be presented.
Citation Format: Deepkamal N. Karelia, Manoj K. Pandey, Daniel Plano, Shantu Amin, Arun K. Sharma. Novel aspirin based selenium compounds as therapy against pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 814. doi:10.1158/1538-7445.AM2014-814
Abstract 815: CBL0137 demonstrates significant antitumor activity against hepatocellular carcinoma alone and in combination with sorafenib
Authors: Burkhart Catherine , Kohrn Rachael , Walker Brittany , Gurova Katerina , Purmal Andrei , Gudkov Andrei 
Published: May 2015

Abstract
Primary hepatocellular carcinoma (HCC) is the 6th most common malignancy diagnosed worldwide with an incidence that continues to rise. Even with the use of the current standard of care drug sorafenib, survival of patients remains at ∼10-11 months and sorafenib toxicity results in dose interruptions and delays. Therefore, tolerable, effective therapies against HCC are greatly needed. CBL0137 represents a novel class of small molecules that simultaneously activate p53 and inhibit cancer-associated stress response pathways, such as NF-κB and HSF-1, and has demonstrated broad range antitumor activity against pre-clinical tumor models. The effects of CBL0137 are mediated by the inhibition of the chromatin remodelling factor FACT (FAcilitates Chromatin Transcription) comprised of SSRP1 and SPT16 subunits. FACT is expressed in undifferentiated progenitors and stem cells of adult tissues, but is almost undetectable in differentiated cells. It is expressed in many tumor types, including HCC, and is correlated with high grade and worse overall survival. Thus, FACT represents a potentially important target for cancer therapy. We investigated the effect of CBL0137 on HCC using HepG2 and Hep3B xenograft models. Treatment of tumor bearing mice intravenously with 60-70 mg/kg CBL0137 every 4th day resulted in ∼88-94% tumor growth inhibition in both models, including tumor regression in 60-80% of tumors during the course of treatment. Furthermore, combination of suboptimal doses of CBL0137 with sorafenib had greater efficacy compared to either drug alone (tumor growth inhibition: HepG2- 87.9% combination vs 73.6% CBL0137 only (P=0.0014), 75.7% sorafenib only (P=0.0006); Hep3B- 79.6% combination vs 38.2% CBL0137 only (P=0.003), 51.4% sorafenib only (P=0.032)). Although the mechanism resulting in the combination effect is unknown, in vitro analysis of markers of CBL0137 and sorafenib activity revealed that both drugs caused a marked decrease in the basal and induced expression of NF-κB target genes (IL-8 and TNF). Furthermore, the combination of CBL0137 and sorafenib almost completely abolished the expression of these genes in both HCC cell lines, suggesting that the combination effect may be in part mediated through inhibition of the NF-κB pathway. Together, these data indicate that CBL0137 may provide a clinical benefit for the treatment of HCC both alone and in combination with sorafenib.
Citation Format: Catherine Burkhart, Rachael Kohrn, Brittany Walker, Katerina Gurova, Andrei Purmal, Andrei Gudkov. CBL0137 demonstrates significant antitumor activity against hepatocellular carcinoma alone and in combination with sorafenib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 815. doi:10.1158/1538-7445.AM2014-815
Abstract 817: Sepantronium is a DNA damaging agent that potentiates PLK1 inhibitor volasertib
Authors: Hong Mei , Ren Mingqiang , Silva Jeane , Hao Zhonglin 
Published: May 2015

Abstract
In a search for novel agents that boost the anti-neoplastic effects of polo-like kinase 1(PLK1) inhibitor volasertib, we found that a sepantronium and volasertib combination at the nano mole concentration potently inhibited growth of various non-small cell lung cancer (NSCLC) cell lines than either drug alone in vitro. Combination use of volasertib with sepantronium inhibited adaptation of cells to polo arrest. Addition of sepantronium to volasertib prevented accumulation of survivin and cyclin B protein at a concentration causing no appreciable survivin down regulation. Sepantronium, was originally developed as a survivin inhibitor. However, sepantronium induced cell cycle arrest from G1 or G2/M phase. Further studies demonstrated DNA damage of cancer cells when they are treated with sepantronium, which is evidenced by induction of phospho-gammaH2AX. In line with induction of a DNA damage response in cancer cells, known DNA damage response sensors and transducers ATM, ATR, CHK1, CHK2, p53 are phosphorylated following drug treatment. Meanwhile, expression of CDKN1A, BAX and XRCC5 are induced at the mRNA level as determined by quantitative real time PCR. A single cell electrophoresis assay (Comet assay) of cells treated with sepantronium revealed severe DNA strand breaks. M-phase arrest does not increase the lethality of DNA damage by sepantronium as compared to G1 phase arrest. Knock down of survivin did not cause DNA damage. Hence, sepantronium is a DNA damaging agent that synergizes with volasertib and down- regulation of survivin is likely the consequence of DNA damage induced by sepantronium.
Citation Format: Mei Hong, Mingqiang Ren, Jeane Silva, Zhonglin Hao. Sepantronium is a DNA damaging agent that potentiates PLK1 inhibitor volasertib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 817. doi:10.1158/1538-7445.AM2014-817
Abstract 819: A novel small molecule cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to treatment with gemcitabine
Authors: Yang Mi Young , Lee Young Bok , Kim Deog Joong , Ahn Chang-Ho , Kaye Joel , Fine Tania , Kashi Rina , Ohne Osnat 
Published: May 2015

Abstract
RX-3117 (fluorocyclopentenylcytosine) is a novel small-molecule chemotherapeutic agent that belongs to the class of cytotoxic antimetabolite cytidine analogs. Cytidine analogs, including gemcitabine, have been widely used for the treatment of various types of cancer, both hematologic as well as solid. However, despite the success of gemcitabine, there is no oral formulation of gemcitabine and drug resistance is common. Thus, RX-3117 was synthesized as a oral formulation to overcome gemcitabine resistance with a better pharmacologic profile. In this study, the efficacy of RX-3117 was examined in 12 different human tumor (colon, non-small cell lung, small cell lung, pancreatic, renal, ovarian and cervical) xenograft models, grown subcutaneously in athymic nude mice. Not only has RX-3117 demonstrated potent efficacy in several cancer xenograft models but also oral treatment with RX-3117 results in dose-dependent tumor growth inhibition (TGI), even in tumors that are only moderately sensitive or resistant to gemcitabine. In the Colo-205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 14%, 25%, and 0% TGI, respectively, whereas oral treatment with RX-3117 induced 93%, 91%, 62%, and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. In order to extend the results established in cell line xenograft models, and to test efficacy in a potentially more clinically relevant system, RX-3117 was evaluated in a single primary low passage human pancreatic Tumorgraft™CTG-0298, which is resistant to gemcitabine and has a favorable RX-3117 activating enzyme profile. Treatment with RX-3117 resulted in dose dependent TGI and was superior to the standard of care agent gemcitabine. This study successfully demonstrated preliminary efficacy and therapeutic potential of RX-3117.
Citation Format: Mi Young Yang, Young Bok Lee, Deog Joong Kim, Chang-Ho Ahn, Joel Kaye, Tania Fine, Rina Kashi, Osnat Ohne. A novel small molecule cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to treatment with gemcitabine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 819. doi:10.1158/1538-7445.AM2014-819
Abstract 821: Fusogenic liposomes: A novel therapeutic strategy to efficiently target and destroy prostate cancer
Authors: Mriouah Jihane , Nesbitt Rae-Lynn , Pink Desmond , Duncan Roy , Zijlstra Andries , Lewis John D. 
Published: May 2015

Abstract
Prostate cancer is the most common malignancy in North American men. While patients have benefited from advances in androgen deprivation therapy, prostate cancer ultimately evolves to a metastatic or castrate-resistant state that makes it the second-leading cause of cancer mortality in males. In the past 3 years, new chemotherapeutic drugs with efficacy in advanced disease have been introduced. Yet their efficacy is limited by dose-limiting toxicities and side effects due primarily to suboptimal biodistribution - they do not target tumors directly. To overcome these limitations, we have developed a novel drug encapsulation system for efficient and specific delivery of chemotherapeutic agents to prostate tumors. The reptilian reovirus-derived fusion-associated small transmembrane (FAST) protein (p14) increases the fusion of liposomes to cell membranes. In this study, we combine these fusogenic liposomes with peptides targeted to gastrin-releasing peptide receptors (GRPR) to improve the delivery of chemotherapeutic payloads specifically to prostate cancer cells while sparing normal tissue.
A fusion protein containing p14 and a C-terminal bombesin peptide was produced in a baculovirus expression system and incorporated into liposomes. The targeting and fusogenic properties of the p14-bombesin protein-containing liposomes were confirmed using flow cytometry. These experiments demonstrated improved delivery to cancer cells in vitro (PC3, LNCaP), compared to non-tumoral cells (BPH). The specificity of targeted fusogenic liposomes was confirmed by knockdown of GRPR and by blocking with free bombesin peptides. We then used intravital imaging in an avian xenograft model to measure the accumulation and specific uptake of the fusogenic targeted liposomes in prostate tumors compared to benign (BPH) and normal tissue, and found a significant increase in uptake in GRPR-expressing prostate cancer tumors using the bombesin-targeted fusogenic liposomes compared to controls. As a further proof of principle, we modified a commercial formulation of Doxil to incorporate our p14-bombesin fusion protein. This formulation showed significantly enhanced cancer-specific cytotoxicity in vitro and increased efficacy in xenograft models.
Taken together, these studies demonstrate that molecular-targeted fusogenic FAST liposomes are a promising platform for improving the efficacy of chemotherapies that should show enhanced activity in advanced and metastatic prostate cancers.
Citation Format: Jihane Mriouah, Rae-Lynn Nesbitt, Desmond Pink, Roy Duncan, Andries Zijlstra, John D. Lewis. Fusogenic liposomes: A novel therapeutic strategy to efficiently target and destroy prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 821. doi:10.1158/1538-7445.AM2014-821
Abstract 830: Disulfiram is a potent inhibitor of topoisomerase II
Authors: Wu Xing , Yalowich Jack C. , Patel Daywin , Hasinoff Brian B. 
Published: May 2015

Abstract
Disulfiram is used in the treatment of alcoholism. It has also shown promise as an anticancer drug. The disulfide bond in disulfiram is metabolized in vivo to diethyldithiocarbamate (DDTC) which forms an extremely strong complex with copper(II) through which it may exert its cytotoxicity. Both disulfiram and diethyldithiocarbamate inhibited K562 cell growth in the low nanomolar range. The addition of the copper(II) chelators Trien and ammonium tetrathiomolybdate to the cell culture medium significantly reduced the cytotoxicity of disulfiram and diethyldithiocarbamate towards K562 cells, which suggests that their cytotoxicity is mediated by uptake of trace amounts of copper from the culture medium. Disulfiram, but not DDTC, strongly inhibited the decatenation activity of topoisomerase IIα in the low micromolar concentration range. Disulfiram, but not DDTC, also was shown to be a topoisomerase IIα poison as evidenced by its ability to induce formation of linear DNA. However, the K/VP.5 cell line, a K562-derived etoposide-resistant cell line with reduced levels of topoisomerase II, was not cross-resistant to either disulfiram or DDTC. K562 cells depleted in GSH levels by treatment with buthionine sulfoximine did not show increased sensitivity to disulfiram or DDTC. Disulfiram and DDTC also did not increase dichlorofluorescein fluorescence in K562 cells. These latter two results suggest that copper-mediated oxidative stress may not be a significant factor in their cytotoxicity. In summary, these results showed that while disulfiram and DDTC inhibited topoisomerase IIα, this inhibition may be only partly responsible for their cytotoxicity. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., and a National Institutes of Health grant CA090787 to J.C.Y.
Citation Format: Xing Wu, Jack C. Yalowich, Daywin Patel, Brian B. Hasinoff. Disulfiram is a potent inhibitor of topoisomerase II. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 830. doi:10.1158/1538-7445.AM2014-830
Abstract 834: The microtubule-disrupting drug BNC105 is a potent inducer of acute apoptosis in CLL
Authors: Bates Darcy J.P. , Feris Edmundo J. , Danilov Alexey V. , Eastman Alan 
Published: May 2015

Abstract
The cytotoxicity of microtubule-disrupting drugs such as the vinca alkaloids has generally been considered to occur during mitosis. However, we have reported that vinca alkaloids can induce apoptosis rapidly (&lt;6 h) from all phases of the cell cycle, and even in post-mitotic quiescent cells such as peripheral chronic lymphocytic leukemia (CLL). Microtubule disruption still appears to be required as acute apoptosis also occurs with combretastatin A4 (CA4) which targets the colchicine-binding site on tubulin, but not with paclitaxel which stabilizes microtubules. The mechanism of this rapid apoptosis is associated with two different pathways: induction of the pro-apoptotic BCL2 family member NOXA and activation of c-Jun N-terminal kinase (JNK). A proof-of-concept clinical trial revealed that vincristine activated JNK in peripheral lymphocytes of patients with CLL, but failed to induce NOXA or apoptosis, suggesting that this might not be the best microtubule disruptor to use clinically. Further investigation revealed that the vascular disrupting agent BNC105 (provided by Bionomics Ltd), which also targets the colchicine-binding site on tubulin, is a much more potent activator of JNK and inducer of NOXA in various leukemia cell lines and freshly isolated CLL cells. BNC105 induced ATF3, phospho-ATF2 and NOXA proteins and activated JNK at low nM concentrations. As a single agent, BNC105 induced JNK-dependent apoptosis in CLL cells ex vivo at clinically achievable concentrations, and much more potently than either vinblastine or CA4. The combination of BNC105 with the BCL2 inhibitor
ABT-199 increased apoptosis levels in CLL cells and various leukemia cell lines. Furthermore, the addition of BNC105 partially overcame stroma-mediated resistance to ABT-199 in CLL cells suggesting potential efficacy of this combination in the lymph node microenvironment. Survival of normal lymphocytes was not affected by BNC alone or in combination, even though JNK was activated. These results suggest BNC105 is an excellent candidate for clinical trials to induce acute apoptosis in hematopoietic malignancies.
Citation Format: Darcy J.P. Bates, Edmundo J. Feris, Alexey V. Danilov, Alan Eastman. The microtubule-disrupting drug BNC105 is a potent inducer of acute apoptosis in CLL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 834. doi:10.1158/1538-7445.AM2014-834