<i>LINCS</i> gene expression signature analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1

Hu, Sai; Xie, Dafei; Zhou, Ping; Liu, Xiaodan; Yin, Xiaoyao; Huang, Bo; Guan, Hua

doi:10.3892/ijmm.2021.4905

Cited by 3 publications

(5 citation statements)

References 40 publications

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“…The cell cycle disruption coincided with lower metabolic activity and an increased rate of apoptosis. It is noteworthy that the radiosensitisation activity of bosutinib is likely more complex as other mechanisms have been reported such as the downregulation of mediators involved in DNA damage response [ 6 ]. In addition, in cells treated with bosutinib-HDL NPs but not irradiated, reduced metabolic activity and increased apoptosis rate were observed despite a lack of significant cell cycle effect.…”

Section: Resultsmentioning

confidence: 99%

“…WEE1 kinase is a key regulator of the G 2 /M cell cycle checkpoint, and small molecule WEE1 inhibitors such as AZD1775 have been shown to be potent radiosensitisers in many cancer types [ 2 , 3 ]. Another potent WEE1 kinase inhibitor is bosutinib (Additional file 1 : Fig S1) [ 4 , 5 ], which has been previously shown to potentiate the effects of DNA damaging agents and radiation [ 6 ]. Bosutinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia but, despite its somewhat favourable toxicity profile compared to other potent tyrosine kinase inhibitors, its use remains commonly associated with dose-limiting side effects including gastrointestinal toxicity and myelosuppression [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Bosutinib high density lipoprotein nanoformulation has potent tumour radiosensitisation effects

et al. 2023

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Disruption of the cell cycle is among the most effective approach to increase tumour cells’ radio-sensitivity. However, the presence of dose-limiting side effects hampers the clinical use of tyrosine kinase inhibitors targeting the cell cycle. Towards addressing this challenge, we identified a bosutinib nanoformulation within high density lipoprotein nanoparticles (HDL NPs) as a promising radiosensitiser. Bosutinib is a kinase inhibitor clinically approved for the treatment of chronic myeloid leukemia that possesses radiosensitising properties through cell cycle checkpoint inhibition. We found that a remarkably high bosutinib loading (> 10%) within HDL NPs could be reliably achieved under optimal preparation conditions. The radiosensitisation activity of the bosutinib-HDL nanoformulation was first assessed in vitro in UM-SCC-1 head and neck squamous cell carcinoma (HNSCC) cells, which confirmed efficient disruption of the radiation induced G2/M cell cycle arrest. Interestingly, the bosutinib nanoformulation out-performed free bosutinib, likely because of the specific affinity of HDL NPs with tumour cells. The combination of bosutinib-HDL NPs and radiotherapy significantly controlled tumour growth in an immunocompetent murine HNSCC model. The bosutinib-HDL nanoformulation also enhanced the radiation induced immune response through the polarisation of tumour associated macrophages towards proinflammatory phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bosutinib high density lipoprotein nanoformulation has potent tumour radiosensitisation effects

et al. 2023

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“…We screened 2040 drugs from a Food and Drug Administration (FDA)-approved drug library and identified bosutinib, a tyrosine kinase inhibitor, as a potential osteogenic agent. Bosutinib is a first-line drug for chronic myeloid leukemia, which acts by targeting oncogene BCR-ABL1. , Additionally, bosutinib can inhibit the growth and metastasis of prostate cancer and serves as a potential radiosensitizer in breast cancer treatment . It belongs to the class of Src-targeting agents, and Src contributes to the regulation of bone homeostasis .…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Additionally, bosutinib can inhibit the growth and metastasis of prostate cancer 9 and serves as a potential radiosensitizer in breast cancer treatment. 10 It belongs to the class of Srctargeting agents, 11 and Src contributes to the regulation of bone homeostasis. 12 Other Src-targeting drugs like dasatinib, saracatinib, ibrutinib, and tofacitinib are reported to inhibit osteoclasts.…”

Section: Introductionmentioning

confidence: 99%

Bosutinib Laden Three-Dimensional Printed Zein Scaffolds Promote Osteogenesis

Zou,

Yin,

Lei

et al. 2024

ACS Appl. Polym. Mater.

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Bone defect repair remains a challenge to be addressed in clinical practice, and existing bone grafting methods still have disadvantages and limitations. Drugs or cytokines laden into bioactive scaffolds to promote bone regeneration is a promising strategy to deal with the problem; thus, it is meaningful to develop drugs and scaffolds with osteogenic abilities. Drug repurposing is an admirable method to find unknown usages of old drugs for enhancing osteogenic differentiation. In this study, by screening an approved drug library consisting of 2040 compounds, bosutinib, a tyrosine kinase inhibitor, was identified to promote osteogenic differentiation in vitro. The observed effect was further confirmed using polymerase chain reaction (PCR), western blot, Alizarin Red staining, and alkaline phosphatase (ALP) activity staining. Subsequently, transcriptome sequencing was performed to elucidate the osteogenesis mechanism of bosutinib, and a potential target gene, Storkhead box 1 (STOX1), which was not reported to be associated with osteogenesis, was found. By a gene knockdown strategy, we provided preliminary evidence that bosutinib can promote osteogenic differentiation by mediating STOX1. Furthermore, in order to maximize the local effects of drug and minimize its side effects, a bosutinib laden three-dimensional (3D)-printed zein scaffold was constructed and characterized, and its ability of promoting osteogenesis was evaluated in vivo. Micro-CT analysis and histological staining demonstrated that the scaffold effectively promoted bone regeneration. All in all, our study provides a therapeutic option for the treatment of bone defects.

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“…In women, breast cancer is the most common malignant tumor and has the highest mortality and morbidity among all malignant tumors worldwide (1)(2)(3)(4). Recently, radiation therapy coupled with breast-conserving surgery has become the standard treatment for many patients with breast cancer (5,6). For patients with breast cancer on the left side, the radiation dose to the heart should be taken into account during radiation therapy because the tumor is relatively close to the heart.…”

Section: Introductionmentioning

confidence: 99%

Application of tangent-arc technology for deep inspiration breath-hold radiotherapy in left-sided breast cancer

Li,

Zhan,

Jia

et al. 2023

Front. Oncol.

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ObjectiveTo explore the advantages of dosimetry and the treatment efficiency of tangent-arc technology in deep inspiration breath-hold radiotherapy for breast cancer.MethodsForty patients with left-sided breast cancer who were treated in our hospital from May 2020 to June 2021 were randomly selected and divided into two groups. The first group’s plan was a continuous semi-arc that started at 145° ( ± 5°) and stopped at 325° ( ± 5°). The other group’s plan, defined as the tangent-arc plan, had two arcs: the first arc started at 145° ( ± 5°) and stopped at 85° ( ± 5°), and the second arc started at 25° ( ± 5°) and stopped at 325° ( ± 5°). We compared the target dose, dose in organs at risk (OARs), and treatment time between the two groups.ResultsThe target dose was similar between the continuous semiarc and tangent-arc groups. The V5 of the right lung was significantly different between the two groups (Dif 5.52, 95% confidence interval 1.92-9.13, t=3.10, P=0.004), with the patients in the continuous semi-arc and tangent-arc groups having lung V5 values of (9.16 ± 1.62)%, and (3.64 ± 0.73)%, respectively. The maximum dose to the spinal cord was (1835.88 ± 222.17) cGy in the continuous semi-arc group and (599.42 ± 153.91) cGy in the tangent-arc group, yielding a significant difference between the two groups (Dif 1236.46, 95% confidence interval 689.32-1783.6, t=4.57, P<0.001). The treatment times was (311.70 ± 60.45) s for patients in the continuous semi-arc group and (254.66 ± 40.73) s for patients in the tangent-arc group, and there was a significant difference in the mean number of treatment times between the two groups (Dif 57.04, 95% confidence interval 24.05-90.03, t=3.5, P=0.001).ConclusionBoth the continuous semi-arc and tangent-arc plans met the clinical prescription dose requirements. The OARs received less radiation with the tangent-arc plan than the continuous semi-arc plan, especially for the lung (measured as V5) and the spinal cord (measured as the maximum dose). Tangent-arc plan took significantly less time than the continuous semi-arc, which can greatly improve treatment efficiency. Therefore, tangent-arc plans are superior continuous semi-arc plans for all cases.

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LINCS gene expression signature analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1

Cited by 3 publications

References 40 publications

Bosutinib high density lipoprotein nanoformulation has potent tumour radiosensitisation effects

Bosutinib high density lipoprotein nanoformulation has potent tumour radiosensitisation effects

Bosutinib Laden Three-Dimensional Printed Zein Scaffolds Promote Osteogenesis

Application of tangent-arc technology for deep inspiration breath-hold radiotherapy in left-sided breast cancer

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