scholarly journals Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models

2012 ◽  
Vol 19 (4) ◽  
pp. 527-539 ◽  
Author(s):  
Barbara Mariniello ◽  
Antonio Rosato ◽  
Gaia Zuccolotto ◽  
Beatrice Rubin ◽  
Maria Verena Cicala ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Viability ◽  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Tumor Cell Line ◽  
Tumor Growth Inhibition ◽  
Adrenocortical Cancer ◽  
Antitumor Effects ◽  
Immunodeficient Mice

Treatment options are insufficient in patients with adrenocortical carcinoma (ACC). Based on the efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of vascular endothelial growth factor and its receptors (VEGFR1–2) was studied in 18 ACCs, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas, and six normal adrenal cortex by real-time PCR and immunohistochemistry and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1–2 were detected in all samples and appeared over-expressed in two-thirds of ACC specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24 h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within ACC. Furthermore, a combination of molecularly targeted agents may have both antiangiogenic and direct antitumor effects and thus could represent a new therapeutic tool for the treatment of ACC.

Imatinib Mesylate Reduces Rituximab-Induced Tumor Growth Inhibition In Vivo on EBV-Associated Human B-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2360-2360
Author(s):  
Fariba Némati ◽  
Claire Mathiot ◽  
Isabelle Grandjean ◽  
Olivier Lantz ◽  
Vincent Bordier ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
B Cell ◽  
Nk Cells ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
B Cell Lymphoma ◽  
Tumor Growth Inhibition ◽  
Immunodeficient Mice

Abstract We previously reported an increase of tumor growth inhibition following chemotherapy combined with concomitantly administration of imatinib mesylate [Decaudin D, et al. Int J Cancer2005;113:849–856; Decaudin D, et al. Anti-Cancer drugs2006;17:685–696; Decaudin D, et al. Impact of STI571 on the pharmacokinetics of etoposide and / or ifosfamide in mice. Cancer Res (AACR Annual Meeting) 2006;abstr:5154]. Inversely, combination of imatinib and rituximab was reported in very few cases of patients and remains controversial. In order to explore this particular combination of targeted therapies, we therefore investigated the in vivo impact of rituximab plus imatinib on a B-cell lymphoproliferation. Combination of the tyrosine kinase inhibitor imatinib mesylate (STI571) and the anti-CD20 monoclonal antibody rituximab was evaluated on an EBV-associated B-cell lymphoproliferative disorder xenografted into SCID or Rag2/gc −/− (B-, T-, and NK-) mice. Using SCID mice, we found that STI571 diminished the efficacy of rituximab to inhibit tumor growth in vivo (Figure 1A). Using alymphoid Rag2/gc −/− mice, we showed that the effect of STI571 was not dependent on the presence of NK cells (Figure 1B). In contrast, serum complement administered after STI571 treatment reversed this inhibitory effect. Finally, using non immunodeficient mice, we observed an in vivo decrease of CD4-positive T-cells and mature B-cell lymphocytes after imatinib administration. We found that STI571 decreased the in vivo efficacy of rituximab via serum protein components that could influence complement-dependent cytotoxicity. In contrast, this effect was not dependent on the presence of NK cells. Figure Figure

Avemar inhibits the growth of mouse and human xenograft mammary carcinomas comparable to endocrine treatments

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21132-21132 ◽  
Author(s):  
M. Tejeda ◽  
D. Gaál ◽  
I. Szűcs ◽  
A. Telekes
Keyword(s):  
Breast Carcinoma ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Estrogen Receptor Status ◽  
Combined Treatment ◽  
Xenograft Model ◽  
The Other ◽  
Endocrine Treatment ◽  
Tumor Growth Inhibition

21132 Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Combination of Avemar with any of the endocrine treatment enhanced the efficacy compared to endocrine monotherapy. Out of the four monotherapies the best result was achieved by Avemar (50% inhibition). The combination of Avemar with Examestane increased the tumor growth inhibition to 60.4% compared to control. The other treatments did not exceed the effect of Avemar monotherapy. In xenograft model Avemar produced 50% tumor growth inhibition compared to control and was more effective than the other treatments Examestane (26%), Anastrasol (25%) or Tamoxifen (42%). Combined treatment with Avemar always improved efficacy within the range of 3–10%. Avemar showed similar efficacy when T47/D (49%) and MDA-MB-231 (52%) xenografts were compared. Conclusions: The tumor growth inhibitory effect of Avemar on ER positive MXT mouse breast carcinoma as well as in T47/D xenograft models are comparable (equal or better) to standard endocrine treatments. Avemar certainly did not reduce the effect of endocrine treatments. The antitumor activity of Avemar did not depend on the estrogen receptor status. No significant financial relationships to disclose.

scholarly journals Antitumor effects of flavopiridol, a cyclin-dependent kinase inhibitor, on human cholangiocarcinoma in vitro and in an in vivo xenograft model

Heliyon ◽  
2019 ◽  
Vol 5 (5) ◽  
pp. e01675 ◽  
Author(s):  
Saowaluk Saisomboon ◽  
Ryusho Kariya ◽  
Kulthida Vaeteewoottacharn ◽  
Sopit Wongkham ◽  
Kanlayanee Sawanyawisuth ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Cyclin Dependent Kinase ◽  
Antitumor Effects ◽  
Cyclin Dependent Kinase Inhibitor

scholarly journals Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model

2019 ◽  
Vol 12 (4) ◽  
pp. 155 ◽  
Author(s):  
Katrine Wickstroem ◽  
Jenny Karlsson ◽  
Christine Ellingsen ◽  
Véronique Cruciani ◽  
Alexander Kristian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Parp Inhibitor ◽  
Xenograft Model ◽  
High Energy ◽  
Tumor Growth Inhibition ◽  
Line Pair

Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.

scholarly journals EXTH-46. ARTIFICIAL INTELLIGENCE-BASED IDENTIFICATION OF COMBINED VANDETANIB AND EVEROLIMUS IN THE TREATMENT OF ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii97-ii97
Author(s):  
Diana Carvalho ◽  
Peter Richardson ◽  
Nagore Gene Olaciregui ◽  
Reda Stankunaite ◽  
Cinzia Emilia Lavarino ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Cell Viability ◽  
Xenograft Model ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Serine Threonine Kinase ◽  
Orthotopic Xenografts ◽  
Extended Survival

Abstract Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of children with the currently incurable brain tumour diffuse intrinsic pontine glioma (DIPG). Treatment of ACVR1-mutant DIPG patient-derived models with multiple inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though there are currently no specific ACVR1 inhibitors licensed for DIPG. Using an Artificial Intelligence-based platform to search for approved compounds which could be used to treat ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits both ABCG2 (BCRP) and ABCB1 (P-gp) transporter, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumour burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Based on these preclinical data, three patients with ACVR1-mutant DIPG were treated with vandetanib and everolimus. These cases may inform on the dosing and the toxicity profile of this combination for future clinical studies. This bench-to-bedside approach represents a rapidly translatable therapeutic strategy in children with ACVR1 mutant DIPG.

The effects of photodynamic therapy with Photodithazine on HPV 16 E6/E7 associated cervical cancer model

2011 ◽  
Vol 15 (03) ◽  
pp. 174-180 ◽  
Author(s):  
Lan Ying Wen ◽  
Su-Mi Bae ◽  
Jin Hwan Do ◽  
Kye-Shin Park ◽  
Woong Shick Ahn
Keyword(s):  
Cervical Cancer ◽  
Photodynamic Therapy ◽  
Growth Inhibition ◽  
Biological Significance ◽  
Light Irradiation ◽  
Tumor Growth Inhibition ◽  
Cancer Model ◽  
Hpv 16

Photodynamic therapy (PDT) is a promising treatment for cancer that has been recently accepted in the clinic. In this study, we examined a biological significance of PDT with a chlorin-based photosensitizer, Photodithazine, on cervical cancer model. When human papillomavirus type 16 (HPV16)- transformed mouse TC-1 cells were exposed to varied doses of Photodithazine with light irradiation (6.25 J/cm2), the significant growth inhibition of TC-1 cells was observed at 0.75 μg/mL of Photodithazine. The damaged cells by Photodithazine/PDT were categorized to be early and late apoptosis, as determined by annexin V staining. Photodithazine was primarily localized at lysosome apparatus within TC-1 cells while it was rapidly accumulated and sustained for initial 3 h in tumor tissue of TC-1 tumor bearing mice after IV injection. The tumor growth inhibition by Photodithazine/PDT with light irradiation (300 J/cm2) was examined after injection of various concentration of Photodithazine in tumor mice system. Our results show that Photodithazine/PDT might have significant advantages in the selective killing of tumor lesions in HPV 16 E6/E7 associated cervical cancer model, both in vitro and in vivo.

scholarly journals Doxorubicin Embedded into Nanofibrillated Bacterial Cellulose (NFBC) Produces a Promising Therapeutic Outcome for Peritoneally Metastatic Gastric Cancer in Mice Models via Intraperitoneal Direct Injection

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1697
Author(s):  
Hidenori Ando ◽  
Takashi Mochizuki ◽  
Amr S. Abu Lila ◽  
Shunsuke Akagi ◽  
Kenji Tajima ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Delivery ◽  
Tumor Growth ◽  
Bacterial Cellulose ◽  
Anticancer Agents ◽  
Intraperitoneal Administration ◽  
In Vitro Release ◽  
Xenograft Model ◽  
Tumor Growth Inhibition

Natural materials such as bacterial cellulose are gaining interest for their use as drug-delivery vehicles. Herein, the utility of nanofibrillated bacterial cellulose (NFBC), which is produced by culturing a cellulose-producing bacterium (Gluconacetobacter intermedius NEDO-01) in a medium supplemented with carboxymethylcellulose (CMC) that is referred to as CM-NFBC, is described. Recently, we demonstrated that intraperitoneal administration of paclitaxel (PTX)-containing CM-NFBC efficiently suppressed tumor growth in a peritoneally disseminated cancer xenograft model. In this study, to confirm the applicability of NFBC in cancer therapy, a chemotherapeutic agent, doxorubicin (DXR), embedded into CM-NFBC, was examined for its efficiency to treat a peritoneally disseminated gastric cancer via intraperitoneal administration. DXR was efficiently embedded into CM-NFBC (DXR/CM-NFBC). In an in vitro release experiment, 79.5% of DXR was released linearly into the peritoneal wash fluid over a period of 24 h. In the peritoneally disseminated gastric cancer xenograft model, intraperitoneal administration of DXR/CM-NFBC induced superior tumor growth inhibition (TGI = 85.5%) by day 35 post-tumor inoculation, compared to free DXR (TGI = 62.4%). In addition, compared with free DXR, the severe side effects that cause body weight loss were lessened via treatment with DXR/CM-NFBC. These results support the feasibility of CM-NFBC as a drug-delivery vehicle for various anticancer agents. This approach may lead to improved therapeutic outcomes for the treatment of intraperitoneally disseminated cancers.

scholarly journals Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetics effects

2021 ◽  
Author(s):  
Ilaria Romito ◽  
Manuela Porru ◽  
Maria Rita Braghini ◽  
Luca Pompili ◽  
Nadia Panera ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Kinase Inhibitor ◽  
Malignant Tumours ◽  
Nurd Complex ◽  
Antitumor Effects ◽  
Combination Regimens

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors, alone or in combination with SOR, using in vitro and in vivo models of HCC. Methods The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was then tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. Results TAE226 emerged as the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of the nuclear interactome of FAK. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation causing an increase of histone H3 lysine 27 acetylation, counteracting its trimethylation by decreasing the nuclear amount of HDAC1/2. Conclusions Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduce HCC growth in vitro and in vivo. Our data also highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising therapeutic approaches for HCC.

scholarly journals Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

2021 ◽  
Author(s):  
Evelyn M. Mrozek ◽  
Vineeta Bajaj ◽  
Yanan Guo ◽  
Izabela Malinowska ◽  
Jianming Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Growth Delay ◽  
Hsp90 Inhibitors ◽  
Null Cell ◽  
Standard Dosage

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored.  Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.

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