bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1683: Novel combination approach using platinum drugs and mitochondrial division inhibitor 1 (mdivi-1) overcomes platinum resistance by synergistically inducing mitochondrial outer membrane permeabilization (MOMP) and apoptosis independent of Drp1
Authors: Qian Wei , Wang Jingnan , Roginskaya Vera , McDermott Lee , Edwards Robert , Stolz Donna , Llambi Fabien , Green Douglas , Houten Bennett Van 
Published: May 2015

Abstract
Platinum based anticancer agents, including cisplatin, are among the most effective and widely used anticancer drugs. However, inherent and acquired resistance to these drugs in tumors lead to treatment failure. We found a class of thioquinazolinone derivatives, including the mitochondrial division inhibitor-1 (mdivi-1), that overcome both the inherent and acquired resistance to cisplatin in tumor cell lines and also in primary ovarian tumors isolated from cisplatin refractory patients. The combination of cisplatin and mdivi-1 produces synergistic effect in inducing rapid apoptosis. Using Drp1 (a mitochondrial fission protein and the reported target of mdivi-1) knockout MEF cells we demonstrated that the combination of cisplatin and mdivi-1 overcomes cisplatin resistance in a Drp1-independent manner. Mdivi-1 causes replication defects and its combination with cisplatin triggers synergistic increases of replication stress and DNA damage. Comparing the treatment with cisplatin and mdivi-1 alone, the combination of the two agents enhances mitochondrial apoptotic signaling by specifically upregulating the expression of a pro-apoptotic Bcl-2 family protein Noxa, which promotes Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Intriguingly, the combination of cisplatin and mdivi-1 also causes mitochondrial swelling that triggers a Bax/Bak-independent MOMP. Thus, the combination of cisplatin and mdivi-1 activates two distinct mechanisms that converge on mitochondria contributing to the enhancement of MOMP. This novel combination represents a potential effective strategy in overcoming platinum drug resistance by combining cisplatin with compounds that together are able to trigger the coinitiation of Bax/Bak-dependent and-independent mitochondrial apoptotic signaling. (Work was supported by P30CA047904, UPCI and PA Dept of Health CURE program)
Citation Format: Wei Qian, Jingnan Wang, Vera Roginskaya, Lee McDermott, Robert Edwards, Donna Stolz, Fabien Llambi, Douglas Green, Bennett Van Houten. Novel combination approach using platinum drugs and mitochondrial division inhibitor 1 (mdivi-1) overcomes platinum resistance by synergistically inducing mitochondrial outer membrane permeabilization (MOMP) and apoptosis independent of Drp1. [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 1683. doi:10.1158/1538-7445.AM2014-1683
Abstract 1684: Histone deacetylase inhibition enhances Pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer models
Authors: Trisciuoglio Daniela , Desideri Marianna , Luca Teresa D. , Martile Marta D. , Gabellini Chiara , Eramo Adriana , Maria Ruggero D. , Milella Michele , Bufalo Donatella Del 
Published: May 2015

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed (PEM), a multi-target folate antagonist, has demonstrated targeted efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS, one of PEM's molecular targets) expression.
Histone deacetylase inhibitors (HDACi) modulate the expression of multiple genes, including thymidylate synthase (TS), one of the main targets of Pemetrexed. Since high levels of TS have been linked to clinical resistance to Pemetrexed in non-small cell lung cancer (NSCLC), we investigated the molecular and functional effects of combined Pemetrexed and ITF2357, a class I/II HDACi currently in clinical trials as anti-cancer agents .ITF2357 reduced TS mRNA and protein expression, potentially affecting sensitivity to Pemetrexed. When the two drugs were used in combiation, their sequence of administration was critical in determining the pharmacologic response: in both NSCLC cell lines and LCSC, a strikingly synergistic reduction in cell viability was observed with the sequence Pemetrexed followed by ITF2357, in both adenocarcinoma and squamous cell carcinoma models. Cell death induced by the combination involved both apoptosis and autophagy. Genetic and pharmacological approaches provided an interesting link between these two pathways and showed that sequential Pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential Pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival.
Overall, this data provide a strong rationale for the clinical development of sequential schedules employing Pemetrexed followed by HDAC inhibition in NSCLC.
Citation Format: Daniela Trisciuoglio, Marianna Desideri, Teresa De Luca, Marta Di Martile, Chiara Gabellini, Adriana Eramo, Ruggero De Maria, Michele Milella, Donatella Del Bufalo. Histone deacetylase inhibition enhances Pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer models. [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 1684. doi:10.1158/1538-7445.AM2014-1684
Abstract 1685: HER2 upregulation induced by gemcitabine treatment augments antitumor effect of trastuzumab emtansine against pancreatic cancer
Authors: Kan Shin , Koido Shigeo , Okamoto Masato , Hayashi Kazumi , Ito Masaki , Kamata Yuko , Komita Hideo , Nagasaki Eijiro , Homma Sadamu 
Published: May 2015

Abstract
[Background]
Although human pancreatic cancer (PC) frequently expresses human epidermal growth factor receptor type 2 (HER2), Trastuzumab has not provided sufficient therapeutic effect on PC probably due to low HER2 expression level. Recently we discovered HER2 expression of human PC cell lines was enhanced by gemcitabine (GEM) treatment. Furthermore, Trastuzumab Emtansine (T-DM1), Trastuzumab conjugated with a cytotoxic agent, showed promising results in breast cancer therapy. We investigated the possibility of new molecular targeting therapy against PC by combined treatment with GEM and T-DM1.
[Materials and Methods]
HER2 expression was analyzed by quantitative Real Time-PCR, western blotting and flowcytometry. The cell proliferation was examined by spectrophotometry using the counting reagents. T-DM1 was provided by Genentech Inc. T-DM1 bindinig to HER2 on PC cell surface was analyzed by flowcytometry.
[Results]
GEM treatment enhanced HER2 expression at around two fold in three out of five human PC cell lines. GEM was the most potent agent to enhance HER2 expression of PC cells among the standard chemotherapeutic agents for PC treatment. T-DM1 binding to HER2 on GEM-treated MiaPaca-2 cells was increased in accordance with the up-regulation of HER2 expression. Combined treatment with GEM and T-DM1 synergistically inhibited the cell growth of MiaPaca-2, and this cytotoxic effect was inhibited by adding to Trastuzumab which did not show direct cytotoxic activity to PC cells.
[Conclusions]
GEM treatment enhances HER2 expression of PC cells which promotes T-DM1 binding to HER2 on PC cells. Combined treatment with GEM and T-DM1 might become a promising modality against HER2 positive PC.
Citation Format: Shin Kan, Shigeo Koido, Masato Okamoto, Kazumi Hayashi, Masaki Ito, Yuko Kamata, Hideo Komita, Eijiro Nagasaki, Sadamu Homma. HER2 upregulation induced by gemcitabine treatment augments antitumor effect of trastuzumab emtansine 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 1685. doi:10.1158/1538-7445.AM2014-1685
Abstract 169: Maintenance of breast cancer stem cells in an inert matrix is mediated by mesenchymal stem cells in the tumor stroma
Authors: Sarvestani Samaneh K. , Barati Danial , Jabbari Esmaiel 
Published: May 2015

Abstract
Introduction: Cancer stem cells (CSCs) hypothesis relates cancer recurrence to a small population of tumor cells with the ability to self-renew to maintain the tumor mass. Recent studies demonstrate that conventional therapies eliminate the differentiated cells that form bulk of the tumor, while leaving CSCs unharmed. There is increasing evidence that the maintenance of CSCs in the tumor tissue is regulated by microenvironment. In particular, human mesenchymal stem cells (hMSCs) and associated soluble factors as part of the tumor stroma play a significant role in self-renewal and maintenance of CSCs (1). Our laboratory has developed an inert 3D synthetic matrix with defined properties that maintains and enriches the CSC sub-population of tumor cells within a certain range of stiffness (2). The objective of this work was to investigate the effect of co-encapsulation of MDA-MB-231 (MDA) human breast cancer cells with human hMSCs in the engineered patterned matrix on tumorsphere formation and CSC maintenance.
Methods: Thee effect of MSCs on MDA cells was investigated in a patterned matrix with defined stiffness to control tumorsphere size. To separate the patterned cellular matrix from the glass substrate, a layer of the gel without cells was first crosslinked on the glass substrate by UV radiation. Next, a mixture of MDA and hMSCs (5x105 cells/mL each) in the hydrogel precursor solution was patterned by UV radiation on the gel covered glass slide with a UV mask. The stiffness of the matrix was controlled by the concentration of macromer in the hydrogel precursor solution. Tumorsphere size and density, and expression of CSC markers were determined with incubation time in tumor CSC culture medium.
Results and Conclusion: The micro-patterned 3D synthetic hydrogel matrix with defined modulus supported tumorsphere formation and expression of CSC markers. Specifically, co-culture of MDA cells with hMSCs increased the expression of CD44 and ABCG2 markers of stemness by three-fold after 6 days of encapsulation in the engineered matrix from 25 to 58 for CD44 and 14 to 42 for ABCG2. Likewise, tumorsphere density more than doubled and average tumorsphere diameter increased from 25 to 47 µm after 6 days of incubation when MDA cells were co-encapsulated with hMSCs. The model inert matrix can be used to understand the effect of individual cell types in the tumor stroma on CSC maintenance and tumorigenesis.
Citation Format: Samaneh K. Sarvestani, Danial Barati, Esmaiel Jabbari. Maintenance of breast cancer stem cells in an inert matrix is mediated by mesenchymal stem cells in the tumor stroma. [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 169. doi:10.1158/1538-7445.AM2014-169
Abstract 1694: Combination of Indolizino[6,7-b]indole and Gefitinib synergistically suppresses the growth of EGFR-mutant NSCLC cells
Authors: Chen Chi-Wei , Tala Satishkumar , Su Tsann-Long , Lee Te-Chang 
Published: May 2015

Abstract
We have previously revealed that indolizino[6,7-b]indoles are effective antitumor agents against a variety of cancer cells. Indolizino[6,7-b]indoles were shown to induce DNA crosslinks and inhibit the enzymatic activities of topoisomerase I and II. Our recent results demonstrated that the derivatives of indolizino[6,7-b]indoles potently suppressed the cell growth of several non-small cell lung cancer (NSCLC) cells, including H460, PC9, PC9/gef B4, and H1975 cells in in vitro and in vivo systems. We also showed that BO-1978, one of indolizino[6,7-b]indole derivatives, completely suppressed the growth of CL1-5/GFP-Luciferase and PC9/gef B4-Luciferase cells in orthotopic lung cancer models. These results implicated that indolizino[6,7-b]indoles are potential candidate agents against NSCLC. EGFR mutations are frequently occurred in NSCLC. Although targeted agents such as Gefitinib is effectively suppression the growth of NSCLC with EGFR mutations, the resistance to Gefitinib is quickly developed and causes the failure of targeted treatments. Since the combination of targeted agents and cytotoxic drugs is one of strategies to overcome the problem encountered by targeted therapy, we further explore the therapeutic potential of combination of BO-1978 and Gefitinib against EGFR-mutant NSCLC. Our results showed that the combination treatment of PC9 and PC9/gef B4 cells with BO-1978 and Gefitinib resulted in synergistic induction of apoptosis and suppression of cell growth in cultured cells. We also confirmed the therapeutic efficacy of combined treatment of PC9 and PC9/gef B4 cells with BO-1978 and Gefitinib in xenografted tumor models. Since we did not observe severe body weight loss in mice received the combination treatment of BO-1978 and Gefitinib, our present studies apparently support that BO-1978 and its combination with Gefitinib is highly prospective as therapeutic agents against EGFR-mutant NSCLC.
Citation Format: Chi-Wei Chen, Satishkumar Tala, Tsann-Long Su, Te-Chang Lee. Combination of Indolizino[6,7-b]indole and Gefitinib synergistically suppresses the growth of EGFR-mutant NSCLC cells. [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 1694. doi:10.1158/1538-7445.AM2014-1694
Abstract 1705: Combinatorial therapeutics with targeting head and neck cancer initiating cells using active components from antrodia cinnamomea and conventional chemotherapy
Authors: Chang Ching-Wen , Lo Jeng-Fan 
Published: May 2015

Abstract
Background: Cancer initiating cells (CICs), also termed as Cancer stem cells (CSCs), represent a rare subpopulation of cells, which are responsible for tumor growth. CICs such as head and neck cancer initiating cells (HN-CICs), are often resistant to either radio- or chemotherapy. Therefore, development for drug candidates that target HN-CICs specifically will be effective for future oral cancer therapy.
Methods: In this study, we used the in vitro cell-based aldehyde dehydrogenase (ALDH) activity assay system, which has been demonstrated as a CICs marker, to screen for the active purified components from Antrodia Camphorata Mycelia extract (ACME), which can target HN-CICs. Next, the antitumorigenicity of combinatorial treatment with active components from ACME and conventional chemotherapy on HNSCC will be examined in vitro and in vivo.
Results: Herein, we first screened for the active components from natural products of ACM significantly down regulate the ALDH activity and CD44 positivity of Head and neck squamous cell carcinoma (HNSCC). Consequently, treatment of YMGKI-2 (analogue of ergosterol), a single and active compound purified from ACME, not only inhibited the ALDH activity but also reduced self-renewal property and expression of stemness genes (Oct-4 and Nanog) in enriched HN-CICs. Moreover, the repressive HN-CICs properties by YMGKI-2 treatment were caused by promoting cell differentiation. Additionally, treatment of YMGKI-2 results in down-regulation of Cox-2 and Src molecular mechanisms which both play important role in CICs. Further, the tumorigenic properties of HNSCC cells were attenuated by YMGKI-2 treatment in vivo. Lastly, combinatorial treatments with YMGKI-2 and standard chemotherapeutic drugs reveal synergistic effects on killing both HN-CICs and non-HN-CICs in vitro and in vivo.
Conclusion: Together, our results indicate that YMGKI-2 treatment significantly and selectively abolished the stemness properties and tumorigenicity of HN-CICs. These findings provide a new drug candidate from purified components of ACM as an alternative therapy in combination with conventional chemotherapy treatment modalities for head and neck cancer in the future.
Citation Format: Ching-Wen Chang, Jeng-Fan Lo. Combinatorial therapeutics with targeting head and neck cancer initiating cells using active components from antrodia cinnamomea and conventional chemotherapy. [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 1705. doi:10.1158/1538-7445.AM2014-1705
Abstract 1716: Targeting the insulin-like growth factor receptor/Insulin receptor and Src signaling network for the treatment of non-small cell lung cancer
Authors: Min Hye-Young , Yun Hye Jeong , Lee Hyo-Jong , Cho Jaebeom , Jang Hyun-Ji , Kim Kyung Min , Kim Woo-Young , Oh Seung-Hyun , Liu Diane , Lee J. Jack , Hong Waun K. , Wistuba Ignacio I. , Lee Ho-Young 
Published: May 2015

Abstract
Insulin-like growth factor I receptor (IGF-1R)-mediated signaling plays an important role in the proliferation, survival, and metastasis of cancer cells. The IGF-1R-targeting anticancer agents including monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) have been developed, but their antitumor effects have been marginal and limited in clinical trials. Therefore, the mechanism underlying resistance to the IGF-1R-targeting therapies and the rational combination strategies to overcome potential drug resistance need to be investigated. In this study, we demonstrated the association of Src with the resistance to the IGF-1R TKI in non-small cell lung cancer (NSCLC). We found the co-activation of IGF-1R/IR and Src in various human NSCLC cell lines, The mRNA expression and phosphorylation of IGF-1R and Src were also significantly correlated with each other in NSCLC databases from a public dataset and a tissue microarray (n=353). Next, we found Src can be activated through multiple pathways including EGFR and integrin β3 signaling and function as an alternative kinase for phosphorylation of IGF-1R, especially at Tyr1135/36, but not Tyr1131. Src is activated in lung cancer cells possessing both primary and acquired resistance to an IGF-1R TKI. Consistent with the results, inhibition of Src significantly attenuated activation of IGF-1R/IR and co-targeting of IGF-1R and Src effectively suppressed cell proliferation, colony formation, and tumor growth in vitro and in vivo. Taken together, these results suggest that Src causes resistance to IGF-1R TKIs by functioning as a key downstream modulator of multiple signaling pathways for IGF-1R phosphorylation and thus co-targeting IGF-1R and Src could be an effective therapeutic strategy for NSCLC.
Citation Format: Hye-Young Min, Hye Jeong Yun, Hyo-Jong Lee, Jaebeom Cho, Hyun-Ji Jang, Kyung Min Kim, Woo-Young Kim, Seung-Hyun Oh, Diane Liu, J. Jack Lee, Waun Ki Hong, Ignacio I. Wistuba, Ho-Young Lee. Targeting the insulin-like growth factor receptor/Insulin receptor and Src signaling network for the treatment of non-small cell lung 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 1716. doi:10.1158/1538-7445.AM2014-1716
Abstract 172: Adipocytes decrease daunorubicin concentration in acute lymphoblastic leukemia cells
Authors: Sheng Xia , Tucci Jonathan , Behan James , Mittelman Steven D. 
Published: May 2015

Abstract
Obesity is associated with increased cancer incidence and mortality. Adipose tissue has been shown to play a role in several types of cancer, including acute lymphoblastic leukemia (ALL). We have demonstrated that murine ALL cells actively migrate into adipose tissue in mice, and that adipocytes protect ALL cells from daunorubicin (DNR) in vitro. We have further shown that media cultured by both adipocytes and ALL cells together (ALCM) can protect ALL cells from DNR. We hypothesize that adipocytes protect ALL cells from DNR by decreasing ALL cell intracellular drug accumulation.
Human pre B ALL cells (BV173) were co-cultured with 3T3-L1 adipocytes using a transwell system. Intracellular DNR was visualized using con-focal fluorescence microscopy at various time points in leukemia cells during DNR treatment. Drug uptake in leukemia cells treated with DNR and co-cultured with adipocytes was measured by flow cytometry. By preloading cells with DNR, drug efflux assays were also performed with ALL cells. Gene expression of ABCB1a and cell surface expression of MDR1 were quantified using qPCR and flow cytometry, respectively, in ALL cells co-cultured with adipocytes.
After 72 hours of DNR treatment, there were significantly more viable BV173 cells in the transwells placed over adipocytes than those over fibroblasts (290,000± 60,500 vs. 108,000± 13,000, p=0.008, n=4). Co-culture with adipocytes was associated with a lower intracellular DNR in BV173 cells. After 4 hours, DNR was 30% lower, and by 24 hours intracellular DNR was 80% less (n=1). However, co-culturing ALL cells with adipocytes was not associated with a significant increase in efflux rate of DNR from preloaded BV173 (half-life = 36±13 vs. 31±9 min., p=0.23, n=3). The mRNA expression of ABCB1a, the gene encoding MDR1, was increased in BV173 cells (130% increase, n=1) co-cultured with adipocytes for 24 hours. However, we did not detect an increase in surface MDR1 expression in BV713 co-cultured with adipocytes.
We then tested whether adipocyte-secreted factors would cause efflux of DNR from ALL cells. There was a tendency for DNR efflux rate to be higher in BV173 cells cultured in ALCM (half-life = 36±13 vs. 27±10 min., p=0.08, n=3). Further investigation is needed to confirm this effect.
These findings demonstrate that adipocytes may protect ALL cells from daunorubicin treatment in part by decreasing intracellular drug accumulation. However, it is not clear whether this effect is due to altered uptake, efflux, or intracellular drug action.
Citation Format: Xia Sheng, Jonathan Tucci, James Behan, Steven D. Mittelman. Adipocytes decrease daunorubicin concentration in acute lymphoblastic leukemia cells. [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 172. doi:10.1158/1538-7445.AM2014-172