scholarly journals Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3699
Author(s):  
Marya Kozinova ◽  
Shalina Joshi ◽  
Shuai Ye ◽  
Martin G. Belinsky ◽  
Dinara Sharipova ◽  
...  
Keyword(s):  
Cell Death ◽  
Gastrointestinal Stromal Tumor ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Single Agent ◽  
Xenograft Model ◽  
Stromal Tumor ◽  
In Vivo Studies ◽  
Preclinical Model ◽  
Kit Mutation

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.

scholarly journals Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

2021 ◽  
Author(s):  
Marya Kozinova ◽  
Shalina Joshi ◽  
Shuai Ye ◽  
Martin G. Belinsky ◽  
Dinara Sharipova ◽  
...  
Keyword(s):  
Cell Death ◽  
Gastrointestinal Stromal Tumor ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Single Agent ◽  
Xenograft Model ◽  
Stromal Tumor ◽  
Preclinical Model ◽  
Akt Inhibitor

AbstractThe majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. AKT is a relevant target for inhibition, in addition to KIT, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated significant synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to cell cycle arrest and cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.

Effects of imatinib vary with the types of KIT-mutation in gastrointestinal stromal tumor cell lines

2005 ◽  
Author(s):  
Kazuhiro Noma ◽  
Yoshio Naomoto ◽  
Mehmet Gunduz ◽  
Junji Matsuoka ◽  
Tomoki Yamatsuji ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Gastrointestinal Stromal Tumor ◽  
Cell Lines ◽  
Stromal Tumor ◽  
Tumor Cell Lines ◽  
Kit Mutation

Efficacy of Panobinostat (LBH589) in CTCL Cell Lines and a Murine Xenograft Model: Defining Molecular Pathways of Panobinostat Activity in CTCL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1375-1375 ◽  
Author(s):  
Wenlin Shao ◽  
Joseph D. Growney ◽  
Yun Feng ◽  
Gregory O’Connor ◽  
Minying Pu ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Tumor Regression ◽  
Single Agent ◽  
Xenograft Model ◽  
Stat Proteins ◽  
Murine Xenograft Model

Abstract Panobinostat (LBH589) is a highly potent oral pan-deacetylase (DAC) inhibitor currently undergoing clinical development in hematologic and solid malignancies. Panobinostat demonstrated preliminary clinical efficacy in cutaneous T-cell lymphoma (CTCL) patients in a phase I trial, with 6 responders out of 10 patients. Here we report the characterization of the effects of panobinostat on CTCL cells in vitro and in a murine xenograft model of CTCL. Panobinostat was found to potently induce growth inhibition of all CTCL cell lines tested (HuT78, HuT102, MJ, and HH) and exhibited significant cytotoxic activity against two CTCL cell lines (HuT78 and HH). Panobinostat was found to induce activation of caspases 3 and 7 in HuT78 and HH cell lines, consistent with its effects on cell viability in these cells. To investigate the effect of panobinostat in vivo, an HH CTCL xenograft mouse model was treated with vehicle or different doses of panobinostat by iv administration qd×5 for 2 weeks. Treatment with panobinostat at 10 mg/kg resulted in complete tumor regression relative to vehicle-treated animals. To gain a better understanding of panobinostat activity in CTCL, molecular mechanisms underlying cell sensitivity or lack thereof were investigated. Inhibition of DAC activity as measured by hyperacetylation of histones H3, H4, and tubulin was observed equally in all four cell lines. Interestingly, CTCL cells insensitive to panobinostat cytotoxicity (HuT102 and MJ) were found to express significantly higher levels of IL-2 receptor and to secrete high levels of select cytokines, including IFN-α, IFN-γ, and TNF-α, as compared with CTCL cells sensitive to panobinostat-induced cytotoxicity. Contrary to panobinostat-sensitive CTCL cells, cells insensitive to panobinostat-induced cell death were found to contain constitutively active NF-κB signaling and elevated activation of STAT proteins. Panobinostat-insensitive HuT102 and MJ cell lines were also found to express high levels of the pro-survival protein Bcl-2, an anti-apoptotic target whose transcription can be activated by NF-κB signaling. Although inhibition of STAT5 activation using a JAK inhibitor did not confer panobinostat sensitivity in the HuT102 and MJ CTCL cell lines, combination of a Bcl-2 inhibitor with panobinostat revealed a synergistic effect on cytotoxicity in these CTCL cells. Such results suggest that blocking anti-apoptotic signaling in combination with panobinostat treatment is effective in conferring panobinostat sensitivity to CTCL cells refractory to panobinostat-induced cell death. These data demonstrate that panobinostat exhibits significant anti-cancer effects on CTCL cells both in vitro and in vivo at clinically attainable concentrations. In addition, we have identified a cellular mechanism of insensitivity to panobinostat and furthermore provided a potential approach for sensitizing cells to panobinostat treatment in combination with a Bcl-2 inhibitor. Panobinostat, as a single agent or in combination, is a promising therapy for CTCL and these studies support continued clinical evaluation of panobinostat in the treatment of CTCL.

scholarly journals Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Oncogene ◽  
2021 ◽  
Vol 40 (11) ◽  
pp. 1957-1973
Author(s):  
Hyunho Yoon ◽  
Chih-Min Tang ◽  
Sudeep Banerjee ◽  
Mayra Yebra ◽  
Sangkyu Noh ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tumor Growth ◽  
Gastrointestinal Stromal Tumor ◽  
Single Agent ◽  
Stromal Tumor ◽  
Paracrine Signaling ◽  
Mesenchymal Transition ◽  
Tumor Growth And Metastasis ◽  
Factor C

AbstractTargeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

scholarly journals Anticancer effects of the combined Thai noni juice ethanolic extracts and 5-fluorouracil against cholangiocarcinoma cells in vitro and in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jeerati Prompipak ◽  
Thanaset Senawong ◽  
Banchob Sripa ◽  
Albert J. Ketterman ◽  
Suppawit Utaiwat ◽  
...  
Keyword(s):  
Nude Mice ◽  
Combination Treatment ◽  
Synergistic Effects ◽  
Single Agent ◽  
Xenograft Model ◽  
Ethanolic Extract ◽  
Model Combination ◽  
Mouse Xenograft Model ◽  
Ethanolic Extracts

AbstractApplication of 5-fluorouracil (5-FU) in cholangiocarcinoma (CCA) is limited by adverse side effects and chemoresistance. Therefore, the combination therapy of 5-FU with other substances, especially natural products may provide a new strategy for CCA treatment. The aim of this study was to evaluate the combination effects of 5-FU and two ethanolic extracts of Thai noni juice (TNJ) products on CCA cell lines and nude mice xenografts. The results of antiproliferative assay showed the combination treatment of 5-FU and each TNJ ethanolic extract exerted more cytotoxicity on CCA cells than either single agent treatment. Synergistic effects of drug combinations can enable the dose reduction of 5-FU. The mechanism underlying a combination treatment was apoptosis induction through an activation of p53 and Bax proteins. In the nude mouse xenograft model, combination treatments of 5-FU with each TNJ ethanolic extract suppressed the growth of CCA cells implanted mice more than single agent treatments with no effects on mouse body weight, kidney, and spleen. Moreover, low doses of TNJ ethanolic extracts reduced the hepatotoxicity of 5-FU in nude mice. Taken together, these data suggested that the ethanolic extracts of TNJ products can enhance the anti-CCA effect and reduce toxicity of 5-FU.

scholarly journals Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3487
Author(s):  
Yu-Ling Lu ◽  
Ming-Hsien Wu ◽  
Yi-Yin Lee ◽  
Ting-Chao Chou ◽  
Richard J. Wong ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Differentiated Thyroid Cancer ◽  
Xenograft Model ◽  
In Vivo Studies ◽  
Follicular Thyroid Cancer ◽  
Biomarker Analysis ◽  
Cancer Tumor

Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in the G2/M phase and apoptosis was induced by adavosertib in the four DTC tumor cell lines. The sensitivity of adavosertib correlated with baseline Wee1 expression. In vivo studies showed that adavosertib significantly inhibited the xenograft growth of papillary and follicular thyroid cancer tumor models. Adavosertib therapy, combined with dabrafenib and trametinib, had strong synergism in vitro, and revealed robust tumor growth suppression in vivo in a xenograft model of papillary thyroid cancer harboring mutant BRAFV600E, without appreciable toxicity. Furthermore, combination of adavosertib with lenvatinib was more effective than either agent alone in a xenograft model of follicular thyroid cancer. These results show that adavosertib has the potential in treating DTC.

scholarly journals Thapsigargin Enhances Cell Death in the Gastrointestinal Stromal Tumor Cell Line, GIST-T1, by Treatment with Imatinib (Glivec)

2006 ◽  
Vol 52 (2) ◽  
pp. 110-117 ◽  
Author(s):  
Toufeng Jin ◽  
Hajime Nakatani ◽  
Takahiro Taguchi ◽  
Hiroshi Sonobe ◽  
Norihito Morimoto ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Gastrointestinal Stromal Tumor ◽  
Cell Line ◽  
Tumor Cell Line ◽  
Stromal Tumor

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

scholarly journals Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2423-2440 ◽  
Author(s):  
Canyu Yang ◽  
Bing He ◽  
Qiang Zheng ◽  
Dakuan Wang ◽  
Mengmeng Qin ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Tumor Burden ◽  
Antitumor Efficacy ◽  
In Vivo Studies ◽  
Immunogenic Cell Death ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tumor Tissues

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

Abstract 1620: Dovitinib has anti-tumor activity in gastrointestinal stromal tumor (GIST) cell lines.

2013 ◽  
Author(s):  
Joseph D. Growney ◽  
Fang Li ◽  
Shumei Qiu ◽  
Bella Gorbatcheva ◽  
Linda Battalagine ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumor ◽  
Cell Lines ◽  
Stromal Tumor ◽  
Anti Tumor Activity
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