Sunitinib malate inhibits intestinal tumor development in male ApcMin/+ mice by down-regulating inflammation-related factors with suppressing β-cateinin/c-Myc pathway and re-balancing Bcl-6 and Caspase-3

Chen, Lai; Xu, Pan; Xiao, Qiuping; Chen, Liling; Li, Shanshan; Jian, Jimo; Zhong, You-Bao

doi:10.1016/j.intimp.2020.107128

Cited by 7 publications

(5 citation statements)

References 62 publications

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“…Notably, treatment with SUN did not affect GI inflammatory scoring compared to control mice. Previously, in a mouse model of intestinal cancer, sunitinib administration at a dosing protocol of 30 mg/kg every other day for 9 weeks resulted in a reduction in various inflammationrelated factors, such as IL-6, IL-1α/1β, TNFα, and IFN-γ at the mRNA level within the GI tract [51]. Alternatively, rats chronically exposed to sunitinib at a lower dose (1.5-15 mg/kg/day) for 13 weeks developed histological evidence of small intestinal injury characterized as glandular hyperplasia that was sometimes associated with inflammation of the intestinal wall; however, those exposed to 0.3-6 mg/kg/day for 6 months had no evidence of GI inflammation [52].…”

Section: Discussionmentioning

confidence: 99%

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

Prebble,

Latka,

Burdekin

et al. 2024

IJMS

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Tyrosine kinase inhibitors (TKIs) may be combined with radiation therapy (RT) to enhance tumor control; however, increased incidences of gastrointestinal (GI) toxicity have been reported with this combination. We hypothesize that toxicity is due to compromised intestinal healing caused by inhibition of vascular repair and proliferation pathways. This study explores underlying tissue toxicity associated with abdominal RT and concurrent sunitinib in a mouse model. Four groups of CD-1 mice were treated with 12 Gy abdominal RT, oral sunitinib, abdominal RT + sunitinib, or sham treatment. Mice received oral sunitinib or the vehicle via gavage for 14 days. On day 7, mice were irradiated with 12 Gy abdominal RT or sham treated. Mice were euthanized on day 14 and intestinal tract was harvested for semiquantitative histopathologic evaluation and immunohistochemical quantification of proliferation (Ki67) and vascular density (CD31). Non-irradiated groups had stable weights while abdominal irradiation resulted in weight loss, with mice receiving RT + SUN having greater weight loss than mice receiving RT alone. Semiquantitative analysis showed significant increases in inflammation in irradiated groups. The difference in the density of CD31+ cells was significantly increased in RT alone compared to SUN alone. Ki67+ density was not significant. In summary, we identify a lack of angiogenic response in irradiated GI tissues when abdominal RT is combined with a TKI, which may correlate with clinical toxicities seen in canine and human patients receiving combined treatment.

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Section: Discussionmentioning

confidence: 99%

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

Prebble,

Latka,

Burdekin

et al. 2024

IJMS

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“…FDA has approved sunitinib for the treatment of renal cell carcinoma and gastrointestinal stromal tumors ( Ebos et al, 2007 ; Brooks et al, 2012 ). In addition, sunitinib also shows activity in clinical studies of neuroendocrine tumors, NSCLC, colon cancer, primary liver cancer, and breast cancer ( Ang et al, 2020 ; Li H et al, 2021 ; Chen et al, 2021 ; Grande et al, 2021 ; Symonds et al, 2021 ). What’s more, sunitinib also has been suggested as a radiosensitizing agent ( Curigliano et al, 2013 ; El Kaffas et al, 2013 ; Affolter et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Xue

et al. 2022

Front. Bioeng. Biotechnol.

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Breast cancer is one of the most common types of cancer. Patients are often concerned about regional recurrence after breast cancer surgery. Radiotherapy plays a vital role in reducing recurrence and prolonging the survival of patients undergoing breast-conserving surgery and high-risk mastectomy. However, 8–15% of patients still have disease progression due to radiation resistance. Therefore, new strategies for combination radiotherapy sensitization must be investigated. In this study, an implantable drug loading system, sunitinib nanoparticles @ matrix metalloproteinases -response hydrogel (NSMRH), uses enzyme-sensitive hydrogel as a carrier to load sunitinib nanoparticles, was identified. The releasing profile demonstrated that sunitinib nanoparticles may be continuously released from the hydrogels. Functional experiments revealed that, when paired with NSMRH, radiation may significantly inhibit tumor cell proliferation, migration, and invasion in vitro. Further animal experiments showed that NSMRH combined with radiotherapy could more effectively control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. Finally, by studying the molecular mechanism of NSMRH, it was hypothesized that in breast cancer cells, NSMRH cooperated with sensitized radiotherapy, mainly due to significantly blocking the G2/M phase, reducing the DNA repair efficiency, inhibiting tumor angiogenesis, promoting apoptosis, and reversing the abnormal expression of platelet-derived growth factor receptor alpha (PDGFRA) after radiotherapy. These findings suggest that NSMRH’s radiation sensitization and anti-tumor activity may aid in the development of a novel method in future clinical applications.

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“…It is pertinent to recall that total number of polyps reported in Apc Min/+ mice vary significantly among different studies. A random examination of 10 publications [40][41][42][43][44][45][46][47][48][49] reporting Apc Min/+ mice tumor numbers around the age of 100 to 110 days showed that the number of small intestinal tumors (mean per mouse) ranged from 55 to 120 in Apc Min/+ mice. The differences in tumor numbers from various research groups could be attributed to facility-dependent housing conditions as well as diet.…”

Section: Discussionmentioning

confidence: 99%

Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the Apc^Min^/+ mouse model

Jala

Bodduluri

Ghosh

et al. 2021

Intl Journal of Cancer

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The biological activities of chemokine (C‐C motif) ligand 2 (CCL2) are mediated via C‐C chemokine receptor‐2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In our study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the ApcMin/+ mouse model. Ablation of CCR2 in ApcMin/+ mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2−/−ApcMin/+ mice exhibited significant reduction in the myeloid cell population and increased interferon γ (IFN‐γ) producing T cells both in spleen and mesenteric lymph nodes compared to ApcMin/+ mice. The CCR2−/−ApcMin/+ tumors showed significantly reduced levels of interleukin (IL)‐17 and IL‐23 and increased IFN‐γ and Granzyme B compared to ApcMin/+ tumors. Transfer of CCR2+/+ApcMin/+ CD4+ T cells into Rag2−/− mice led to development of colitis phenotype with increased CD4+ T cells hyper proliferation and IL‐17 production. In contrast, adoptive transfer of CCR2−/−ApcMin/+ CD4+ T cells into Rag2−/− mice failed to enhance colonic inflammation or IL‐17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL‐17 producing cells mediating tumor‐promoting inflammation in addition to its role in migration of tumor associated macrophages.

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Sunitinib malate inhibits intestinal tumor development in male ApcMin/+ mice by down-regulating inflammation-related factors with suppressing β-cateinin/c-Myc pathway and re-balancing Bcl-6 and Caspase-3

Cited by 7 publications

References 62 publications

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the Apc^Min^/+ mouse model

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Sunitinib malate inhibits intestinal tumor development in male ApcMin/+ mice by down-regulating inflammation-related factors with suppressing β-cateinin/c-Myc pathway and re-balancing Bcl-6 and Caspase-3

Cited by 7 publications

References 62 publications

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model

Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity

Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the ApcMin/+ mouse model

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Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the Apc^Min^/+ mouse model