Combining radiation with PI3K isoform-selective inhibitor administration increases radiosensitivity and suppresses tumor growth in non-small cell lung cancer

Seol, Mi Youn; Choi, Sang-Bang; Yoon, Hong In

doi:10.1093/jrr/rrac018

Cited by 4 publications

(6 citation statements)

References 71 publications

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“…Epithelial–mesenchymal transition (EMT) is known to be increased in tumors that have acquired radioresistance. 23 Therefore, we confirmed that inhibition of the PI3K isoform inhibits GBM migration ability and regulates EMT-related gene expression in vitro ( Supplementary Fig. 3 , only online).…”

Section: Discussionsupporting

confidence: 65%

“… 17 37 38 In our previous study, we confirmed that the inhibition of the PI3K-α isoform in NSCLC improves radiosensitivity, thereby increasing the radio-therapeutic response of tumors and suppressing EMT. 23 This suggests that PI3K-α inhibitors have promising safety and may be effective agents to increase the response rate to radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…We used the same doses of these inhibitors as used in our previous study. 23 All chemicals were purchased from Selleckchem (Houston, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

“… 13 22 Our previous study demonstrated that the selective inhibition of PI3K isoforms enhances radiosensitivity in non-small cell lung cancer. 23 …”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity

et al. 2023

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Purpose Glioblastoma (GBM) is a malignant brain tumor with poor prognosis. Radioresistance is a major challenge in the treatment of brain tumors. The development of several types of tumors, including GBM, involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Upon activation, this pathway induces radioresistance. In this study, we investigated whether additional use of selective inhibitors of PI3K isoforms would enhance radiosensitivity in GBM. Materials and Methods We evaluated whether radiation combined with PI3K isoform selective inhibitors can suppress radioresistance in GBM. Glioma 261 expressing luciferase (GL261- luc ) and LN229 were used to confirm the effect of combination of radiation and PI3K isoform inhibitors in vitro. Cell viability was confirmed by clonogenic assay, and inhibition of PI3K/AKT signaling activation was observed by Western blot. To confirm radiosensitivity, the expression of phospho-γ-H2AX was observed by immunofluorescence. In addition, to identify the effect of a combination of radiation and PI3K-α isoform inhibitor in vivo, an intracranial mouse model was established by implanting GL261- luc . Tumor growth was observed by IVIS imaging, and survival was analyzed using Kaplan–Meier survival curves. Results Suppression of the PI3K/AKT signaling pathway increased radiosensitivity, and PI3K-α inhibition had similar effects on PI3K-pan inhibition in vitro. The combination of radiotherapy and PI3K-α isoform inhibitor suppressed tumor growth and extended survival in vivo. Conclusion This study verified that PI3K-α isoform inhibition improves radiosensitivity, resulting in tumor growth suppression and extended survival in GBM mice.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

“…We used the same doses of these inhibitors as used in our previous study. 23 All chemicals were purchased from Selleckchem (Houston, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

“… 13 22 Our previous study demonstrated that the selective inhibition of PI3K isoforms enhances radiosensitivity in non-small cell lung cancer. 23 …”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity

et al. 2023

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“…Emerging data showed that the PI3K/AKT/mTOR pathway can be a therapeutic target for NSCLC [ 20 , 21 ]. The activation of the PI3K/AKT pathway can enhance tumor vascularization and tumor growth [ 22 ], while inhibitors of this pathway can significantly inhibit lung cancer development [ 23 , 24 ]. HIF-1 α is a transcription factor widely expressed in humans under hypoxic environments and is highly expressed in most tumor tissues [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

WDR72 Enhances the Stemness of Lung Cancer Cells by Activating the AKT/HIF-1α Signaling Pathway

Ouyang

Shi

Huang

et al. 2022

Journal of Oncology

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Objectives. Lung cancer is a common malignant tumor with high morbidity and mortality rate. Lung cancer stem cells are crucial in the development of lung cancer. In this study, we investigate WD repeat-containing protein 72 (WDR72) on lung cancer cell stemness and explore its underlying mechanism. Methods. WDR72 expression was investigated in lung cancer tissues and lung cancer stem cells by Western blot and RT-qPCR. The stemness of lung cancer stem cells was verified by the sphere-forming experiment and the abundance of stem cell markers. For the purpose of determining lung cancer stem cell growth, metastasis, and apoptosis, the CCK-8 assay, colony formation, Transwell migration, and flow cytometry were carried out. The ability of tumorigenesis in vivo was explored by xenograft tumor mouse models. Results. Up-regulation of WDR72 was found in lung cancer tissues and lung cancer stem cells. WDR72 overexpression significantly activated the AKT/HIF-1α signaling pathway. Application of PI3K/AKT pathway inhibitor LY29004 was able to counteract the impacts of WDR72 upregulation on genes related to stemness, growth, migration, and apoptosis in lung cancer stem cells. The sphere formation of lung cancer stem cells was significantly diminished after inhibiting the AKT/HIF-1α pathway. The promotion of WDR72 overexpression on lung cancer stem cell proliferation and metastasis was also eliminated by LY29004 treatment. Conclusion. WDR72 activates the AKT/HIF-1α signaling pathway to enhance the stemness of lung cancer stem cells and promote the growth and metastasis of lung cancer.

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Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited

Byskata

Lukoseviciute

Tuti

et al. 2022

Cancers

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Human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC/BOTSCC) is rising in incidence, but chemoradiotherapy is not curative for all. Therefore, targeted therapy with PI3K (BYL719), PARP (BMN-673), and WEE1 (MK-1775) inhibitors alone or combined was pursued with or without 10 Gy and their effects were analyzed by viability, proliferation, and cytotoxicity assays on the TSCC/BOTSCC cell lines HPV+ UPCI-SCC-154 and HPV− UT-SCC-60A. Effective single drug/10 Gy combinations were validated on additional TSCC lines. Finally, APR-246 was assessed on several TSCC/BOTSCC cell lines. BYL719, BMN-673, and MK-1775 treatments induced dose dependent responses in HPV+ UPCI-SCC-154 and HPV− UT-SCC-60A and when combined with 10 Gy, synergistic effects were disclosed, as was also the case upon validation. Using BYL719/BMN-673, BYL719/MK-1775, or BMN-673/MK-1775 combinations on HPV+ UPCI-SCC-154 and HPV− UT-SCC-60A also induced synergy compared to single drug administrations, but adding 10 Gy to these synergistic drug combinations had no further major effects. Low APR-246 concentrations had limited usefulness. To conclude, synergistic effects were disclosed when complementing single BYL719 BMN-673 and MK-1775 administrations with 10 Gy or when combining the inhibitors, while adding 10 Gy to the latter did not further enhance their already additive/synergistic effects. APR-246 was suboptimal in the present context.

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Combining radiation with PI3K isoform-selective inhibitor administration increases radiosensitivity and suppresses tumor growth in non-small cell lung cancer

Cited by 4 publications

References 71 publications

Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity

Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity

WDR72 Enhances the Stemness of Lung Cancer Cells by Activating the AKT/HIF-1α Signaling Pathway

Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited

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