bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 946: Mitochondrial division inhibitor 1 (mdivi-1) overcomes cisplatin resistance independent of dynamin-related protein 1 (Drp1).
Authors: Qian Wei , Roginskaya Vera , Strychor Sandra , Beumer Jan , McDermott Lee , Wang Jingnan , Van Houten Bennett 
Published: August 2014

Abstract
Platinum based anticancer agents including cisplatin are among the most effective and widely used anticancer drugs. However, the inherent and acquired resistance to these drugs in tumors present significant challenges in cancer treatment and directly lead to treatment failure. We have identified a number of thioquinazolinone derivatives, including the mitochondrial division inhibitor-1 (mdivi-1), that are able to effectively overcome both the inherent and acquired resistance to cisplatin and induce rapid apoptosis in several tumor cell lines. However, the enhanced cellular sensitivity to cisplatin by mdivi-1 was also observed in Drp1 (a mitochondrial fission protein and the supposed target of mdivi-1) knockout MEF cells, indicating Drp1-independent roles of these compounds in overcoming platinum drug resistance. The combination of cisplatin and mdivi-1 induces a robust replication stress response and enhances both intrinsic and extrinsic apoptotic signaling when compared with cisplatin or mdivi-1 treatment alone. Though the combined effect of cisplatin and mdivi-1 is not dependent on mitochondrial fission protein Drp1, mitochondria do play a significant role in the rapid execution of apoptosis triggered by this combination. Highly uncoupled mitochondria, increased generation of reactive oxygen species (ROS) and the release of apoptotic factors were observed only in cells treated with the combination of cisplatin and mdivi-1 and not in cells treated with the compounds individually. Taken together, we have identified novel functions for a set of thioquinazolinone derivatives that are able to overcome platinum drug resistance through enhancing replication stress-mediated apoptotic response.
Citation Format: Wei Qian, Vera Roginskaya, Sandra Strychor, Jan Beumer, Lee McDermott, Jingnan Wang, Bennett Van Houten. Mitochondrial division inhibitor 1 (mdivi-1) overcomes cisplatin resistance independent of dynamin-related protein 1 (Drp1). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 946. doi:10.1158/1538-7445.AM2013-946
Abstract 959: Attenuation of hypoglycemia-associated resistance to PI103 and KU63794 through their synergistic combination in PIK3CA-mutant gastric cancer cells.
Authors: Bhattacharya Bhaskar , Low Sarah , Yee Meiqi , Koh King Xin , Soong Richie 
Published: August 2014

Abstract
Drug testing in vitro has traditionally been performed in hyperglycemic culture conditions, yet many tumours and their microenvironments are hypoglycemic. Hypoglycemia could contribute to drug resistance through many mechanisms such as activation of stress and survival pathways, and by altering tumour bioenergetics. The aim of this study was to evaluate if hypoglycemia reduces drug sensitivity, and test strategies to attenuate any resistance. Two gastric cancer (GC) cells with PIK3CA mutations (AGS, HGC27) and two without (MKN45, NUGC4) were cultured in routine high glucose (HG) (25mM) or low glucose (LG) (5mM) DMEM. The IC50s of PI103 (PI3K/mTOR inhibitor), and KU63794 (mTOR inhibitor) were measured at 72h using MTS assay. Protein and cell cycle analysis were performed by ELISA and PI/RNase staining respectively. Combination analysis was performed using combination index (CI) method of Chou and Talalay. Cells with mutant (mt) but not wildtype (wt) PIK3CA displayed significant resistance to both PI103 and KU63794 in LG compared to HG conditions (Table 1), despite having similar doubling times and cell cycle profiles. Basal protein analysis revealed increased p-mTOR, p-S6, p-4EBP1 and GLUT1 in PIK3CA mt cells grown in LG compared to HG conditions. The levels of these proteins did not differ in PIK3CA wt cells, in addition to p-Akt in all cells. The activation of the mTOR pathway prompted the testing of the combination of PI103 and KU63794. The combination was synergistic in AGS and HGC27 cells (CI=0.09, p=0.012 and CI=0.13, p=0.032 respectively) in LG conditions, and additive in HG conditions. Furthermore, synergy was associated with significant reduction in p-4EBP1 and extracellular lactate concentration. No synergy was seen in the wt cell lines. These results suggest that hypoglycemia can reduce drug sensitivity, and that resistance to PI103 and KU63794 in hypoglycemic conditions can be circumvented by combining the two agents.
Table 1. IC50 (μM) of PI103 and KU63794 in HG and LG conditions, * p &lt; 0.01 Cell Line PIK3CA PI103 (HG) PI103 (LG) KU63794 (HG) KU63794 (LG) AGS Mutant 0.90 ± 0.02 7.2 ± 1.4* 0.5 ± 0.03 18.1 ± 1.3* HGC27 Mutant 0.45 ± 0.01 6.8 ± 0.4* 0.37 ± 0.01 20.1 ± 2.4* NUGC4 Wildtype 21.3 ± 4.7 22.4 ± 3.8 8.7 ± 6.5 6.9 ± 7.9 MKN45 Wildtype 1.8 ± 0.9 2.3 ± 1.8 3.4 ± 0.8 2.4 ± 0.6
Citation Format: Bhaskar Bhattacharya, Sarah Low, Meiqi Yee, King Xin Koh, Richie Soong. Attenuation of hypoglycemia-associated resistance to PI103 and KU63794 through their synergistic combination in PIK3CA-mutant gastric cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 959. doi:10.1158/1538-7445.AM2013-959
Abstract 964: Gefitinib resistance due to STAT3-mediated Akt activation in lung cancer cells.
Authors: Wu Kai , Lu Yongju , Chen Bailing , Chang Qingshan , Qiu Ping , Yu Miaomiao 
Published: August 2014

Abstract
Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, are effective drugs for a subset of non-small cell lung cancer. Gefitinib binds to the tyrosine kinase domain of EGFR and hence inactivates its downstream prosurvival signaling pathways, including PI3k/Akt and MAPK pathways. However, most patients received gefitinib eventually developed resistance to this drug. In this study, we demonstrated that in gefitinib-treated A549 cells (human lung cancer cell line), Akt activation undergoes a time-dependent recovery following an initial inhibition by gefitinib. Since constant activation of Akt has been associated with treatment failure of gefitinib in lung cancer cells, exploring the mechanisms that lead to Akt restoration should provide new insights into the drug resistance and therapeutic efficacy. For that purpose, alterations in Akt activation and other signaling pathways, including MAPK and STAT3, involved in EGFR-mediated cellular responses were determined in A549 cells treated with gefitinib. Among them, we found that activation of STAT3 was inhibited in the cells without gefitinib treatment. Gefitinib treatment inhibited EGFR phosphorylation on tyrosine 1086 (Y1086), which leads to STAT3 activation. Further studies showed that interruption of the STAT3 signaling by either chemical inhibitor or siRNA against STAT3 prevented fast recovery of Akt activation and enhanced gefitinib-induced suppression of cell proliferation. Taken together, these data suggest that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFR TKIs. Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs on lung cancer.
Citation Format: Kai Wu, Yongju Lu, Bailing Chen, Qingshan Chang, Ping Qiu, Miaomiao Yu. Gefitinib resistance due to STAT3-mediated Akt activation in lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 964. doi:10.1158/1538-7445.AM2013-964
Abstract 973: Salinomycin sensitized paclitaxel-resistant human ovarian cancer cells and induced apoptosis.
Authors: Cho Chi-Heum , Lee Hyun-Gyo , Parajuli Bidur , Shin So-Jin , Kwon Sang-Hoon , Cha Soon-Do 
Published: August 2014

Abstract
Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world.
Drug resistance is the main cause of treatment failure and mortality in cancer patients. The objective of this study was to establish a paclitaxel (PTX)-resistant human ovarian carcinoma cell line (OVCAR3) and to sensitize chemoresistant cells. The drug-resistant tumor cell lines were established in vitro by stepwise sequential exposure to increased concentration of PTX. For sensitization, OVCAR3/PTX cells were treated with different concentration of salinomycin alone or combined with PTX. The cell viability and cell cycle distribution was measured by MTT and flow cytometric analysis. The transcriptional change of mRNA was examined by RT-PCR.
The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay and western blot analysis. The cell viability was significantly reduced by combination treatment in a dose dependent manner. The flow cytometry result showed an increase in sub-G1 phase. Combination treatment enhanced the sensitivity of OVCAR3/PTX cells to PTX with down-regulation of P-glycoprotein,
XIAP and survivin. Taken together, we demonstrated potential effect of salinomycin in sensitization of PTX resistant ovarian tumor growth. Our results suggest salinomycin in combination with PTX may be a beneficial chemotherapeutic strategy, especially in patients with tumors refractory to PTX alone.
Citation Format: Chi-Heum Cho, Hyun-Gyo Lee, Bidur Parajuli, So-Jin Shin, Sang-Hoon Kwon, Soon-Do Cha. Salinomycin sensitized paclitaxel-resistant human ovarian cancer cells and induced apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 973. doi:10.1158/1538-7445.AM2013-973
Abstract 975: Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump..
Authors: Mazard Thibault , Causse Annick , Simony Joelle , Leconet Wilhem , Jarlier Marta , Ychou Marc , Del Rio Maguy , Martineau Pierre , Robert Bruno , Gongora Céline 
Published: August 2014

Abstract
Background: Despite recent advances in the treatment of colorectal cancer, tumor resistance is a frequent cause of chemotherapy failure. Thus, new treatment options are needed to improve survival of patients with irinotecan-refractory colorectal cancers, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy.
Materials and methods: We used both in vitro (the HCT116, SW48, SW620 and HT29 colon adenocarcinoma cell lines and four SN-38 resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38 resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan, or its active metabolite SN-38.
Results: Sorafenib improved the anti-tumoral activity of irinotecan in vitro, in both parental and SN-38 resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity.
Conclusion: Our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in colorectal cancer, particularly in KRAS mutated tumors.
Citation Format: Thibault Mazard, Annick Causse, Joelle Simony, Wilhem Leconet, Marta Jarlier, Marc Ychou, Maguy Del Rio, Pierre Martineau, Bruno Robert, Céline Gongora. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 975. doi:10.1158/1538-7445.AM2013-975
Abstract 983: A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines.
Authors: Sato Hiromi , Siddig Sana , Suzuki Rina , Uzu Miaki , Suzuki Sayumi , Nomura Yuki , Sekine Yuko , Uehara Tomoya , Arano Yasushi , Ueno Koichi 
Published: August 2014

Abstract
Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) and currently approved for use in advanced renal cell carcinoma (RCC). It is really attractive drug for patients who cannot have surgical treatment. However, it is reported that TKI might be substrates of ATP-binding cassette (ABC) transporters, which are able to mediate the efflux of anti-tumor drugs from the tumor cells. In this study, we suggested that inhibition of MDR transporters by elacridar (dual inhibitor of MDR-1 and ABCG2) might overcome sunitinib resistance in experimental RCC.
We used 786-O and Caki-1 RCC cell lines. The cells were treated with sunitinib alone, elacridar alone or the combination, then cytotoxicity was measured by the MTT cytotoxicity method. The expression of MDR-1 and ABCG2 mRNA and their protein were detected by real time RT-PCR or Western blotting. Additionally, P-gp function was analyzed by using 99mTc-MIBI. MCF-7 cells were used as negative control for P-gp functional assay.
Our results showed that elacridar significantly enhanced sunitinib cytotoxicity in RCC cells. High P-gp expression was especially observed in 786-O, though that of ABCG2 was almost the same among cells. Additionally P-gp assay revealed that the protein would be active and elacridar blocked its function in 786-O, where the accumulation of the 99mTc-MIBI increased 7 folds compared to the control (non-treatment group).
These findings suggest that sunitinib resistance is partly mediated by gene and protein expression of MDR transporters. Therefore combination with elacridar could reverse its resistance in MDR sensitive cancer cells, as it did in 786-O.
Citation Format: Hiromi Sato, Sana Siddig, Rina Suzuki, Miaki Uzu, Sayumi Suzuki, Yuki Nomura, Yuko Sekine, Tomoya Uehara, Yasushi Arano, Koichi Ueno. A dual inhibitor of MDR-1 and ABCG2,elacridar, enhances cytotoxic effects of sunitinib on RCC cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 983. doi:10.1158/1538-7445.AM2013-983
Abstract 984: The role of TGF-alpha in the resistance to mesothelioma chemotherapy.
Authors: Neelature Sriramareddy Sathya , Vandermeers Fabian , Costa Chrisostome , Mascaux Céline , Scherpereel Arnaud , Delvenne Philippe , Hubert Pascale , Willems Luc L. 
Published: August 2014

Abstract
Background. Malignant mesothelioma (MM) is a cancer of the pleura caused mainly by the inhalation of asbestos fibers. The impact of chemotherapy on the outcome of patients with MM is still unclear. We hypothesized that unresponsiveness to chemotherapy is due to inadequate gene expression in tumor cells. We have previously shown that inhibitors of histones deacetylases (such as valproate, VPA) significantly increases the efficacy of compounds used in chemotherapy (Vandermeers et al, 2010, Clinical Cancer Research 15: 2818). A recent clinical trial on relapsing MM patients has shown that VPA in combination with doxorubicin improves response rates and quality of life (Scherpereel et al, 2011, European Respiratory Journal 37:129).
Results. To study the mechanisms associated with the response to chemotherapy, we compared two types of cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Using Agilent microarrays and RT-qPCR, we observed that the basal expression level of TGFα was higher in "resistant" H28 compared to "sensitive" M14K cells. To evaluate the functional relevance of TGFα, we modulated its expression either by RNA interference or by transfection of a cDNA vector. A decrease of TGFα expression correlated with induction of apoptosis. Inversely, an inhibition of apoptosis occurred when TGFα was over-expressed. As TGFα is the ligand of EGFR, we tested the effect of gefitinib and erlotinib in combination with VPA+doxorubicin. Both EGFR inhibitors increased apoptosis induced by VPA+doxorubicin in H28 chemoresistant cells. Finally, the VPA+doxorubicin+erlotinib regimen prevented tumor growth in two mouse models (ZL34 in SCID and AB12 in Balb/c).
Conclusions. Our data demonstrates that TGFα is involved in the chemoresistance to VPA+doxorubicin, a second-line regimen for MM. Although inefficient alone, tyrosine kinase inhibitors synergize to induce apoptosis in chemoresistant cells and prevent tumor growth in mouse models.
Citation Format: Sathya Neelature Sriramareddy, Fabian Vandermeers, Chrisostome Costa, Céline Mascaux, Arnaud Scherpereel, Philippe Delvenne, Pascale Hubert, Luc L. Willems. The role of TGF-alpha in the resistance to mesothelioma chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 984. doi:10.1158/1538-7445.AM2013-984
Abstract 986: Sildenafil potentiates the anticancer activity of paclitaxel in ABCB1-mediated multidrug resistance xenograft model.
Authors: Sodani Kamlesh , Tiwari Amit K. , Dai Chun-ling , Abuznait Alaa H. , Xiao Zhi-jie , Kaddouni Amal , Chen Zhe-Sheng 
Published: August 2014

Abstract
The multidrug resistance (MDR) phenotype caused by the overexpression of ATP-binding cassette (ABC) transporters promotes the cellular efflux of a variety of anticancer drugs that may lead to cancer treatment failure. Previous in vitro studies from our group reported sildenafil, a PDE-5 inhibitor, could significantly block the function of ABCB1/P-glycoprotein and reverse ABCB1/P-glycoprotein-mediated MDR. In the current study we investigated the effect of sildenafil on the ABCB1-mediated MDR in vivo. To determine this effect we developed ABCB1-xenograft nude muse model using ABCB1 overexpressing KB-C2 cell line. We found that sildenafil significantly enhanced the chemotherapeutic response of paclitaxel in the ABCB1-xenograft nude mouse model. The combination treatment with sildenafil and paclitaxel attenuated the tumor growth synergistically. In addition, there was no visible toxicity, weight loss or other gross phenotypic changes with combination treatment. The positive effects of sildenafil can be attributed to inhibition of ABCB1-mediated drug efflux. This phenomenon was further supported by increased concentrations of paclitaxel in ABCB1-overexpressing tumors in the combination treatment group compared to paclitaxel alone. In addition, pharmacokinetic analysis showed increase in the plasma paclitaxel concentration in the combination group. These beneficial actions of sildenafil can be considered as viable option for combination therapy with the clinical anticancer drugs that succumb to ABCB1-mediated insensitivity.
Citation Format: Kamlesh Sodani, Amit K. Tiwari, Chun-ling Dai, Alaa H. Abuznait, Zhi-jie Xiao, Amal Kaddouni, Zhe-Sheng Chen. Sildenafil potentiates the anticancer activity of paclitaxel in ABCB1-mediated multidrug resistance xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 986. doi:10.1158/1538-7445.AM2013-986
Abstract 988: F14512, a novel vectorized topoiserase II inhibitor, bypasses MDR1 mediated resistance.
Authors: Annereau Jean Philippe , Brel Viviane , Riquet William , Créancier Laurent , Vandenberghe Isabelle , Fournier Emmanuel , Robichon Céline , Stennevin Aline , Offrete Vanessa , Lacastaigneratte Laurence , Gomes Bruno , Kruczynski Anna , Bailly Christian , Guilbaud Nicolas 
Published: August 2014

Abstract
F14512 is a novel polyamine-vectorized topoisomerase II inhibitor currently in phase 1/2 clinical trial in acute myeloid leukemia (AML). Since ABCB1 (also called P-glycoprotein or MDR1) has been reported to be expressed at high levels in patients with resistant leukaemia cells, and constitutes a pejorative marker of therapy, we decided to investigate whether F14512 could be exported by ABCB1 or other ABC transporters susceptible to confer drug resistance to chemotherapy, such as MRP1. In addition, we established a F14512-resistant cell line to study the mechanism of resistance to the drug.
With membrane preparation enriched in functional MDR1, we found that F14512 was unable to stimulate the ATPase activity of this transporter. Using a cellular assay over expressing MDR1 transporter by recombinant transfection of MDCKII cells, F14512 was detectable, but the intracellular level was unchanged regardless of the MDR1 status or in presence of MDR1 competitors. Consistently, iterative selection of a F14512-resistant A-549 cell line with 36 cycles of F14512 at cytotoxic doses (0.5 EC50) over 9 months, led to only moderate shift of resistance (9 fold). In the resulting selected A-549 subclones, MDR1, MRP1 and ABCG2 were detectable at the basal level.
The ability of F14512 to bypass MDR1 was finally assessed in a vinorelbine-resistant P388 model overexpressing high level of functional ABCB1 as indicated with the positive rhodamine export assay and cross resistance to MDR1 substrate. Moreover, F14512 displays strong antileukemic activity in MDR1-positive P388 cells in vitro and additional in vivo measurements are in progress.
In conclusion, the data concur to show that the antitumor activity of the targeted cytotoxic agent F14512 is not impacted by the MDR1 status of cancer cells. MDR1 clearly does not affect the potency of F14512 and this characteristic augurs well for the ongoing development of the drug in AML patients.
Citation Format: Jean Philippe Annereau, Viviane Brel, William Riquet, Laurent Créancier, Isabelle Vandenberghe, Emmanuel Fournier, Céline Robichon, Aline Stennevin, Vanessa Offrete, Laurence Lacastaigneratte, Bruno Gomes, Anna Kruczynski, Christian Bailly, Nicolas Guilbaud. F14512, a novel vectorized topoiserase II inhibitor, bypasses MDR1 mediated resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 988. doi:10.1158/1538-7445.AM2013-988