Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons

Hussain, Rumana; Coupland, Sarah E.; Khzouz, Jakub; Kalirai, Helen; Parsons, Jason L.

doi:10.3390/cancers12061388

Cited by 10 publications

(9 citation statements)

References 30 publications

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“…Mel270 originated from a recurrent tumor after prior irradiation and thus escaped radiation therapy [7]. Previous studies have confirmed that Mel270 spheroids are less responsive to radiation and electrochemotherapy with bleomycin compared to other UM cell lines 92-1, UPMD2, or UPMM3 [32,36]. However, in the present study, the tumor control of Mel270 spheroids was achieved by carvedilol treatment.…”

Section: Discussioncontrasting

confidence: 48%

The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation

Farhoumand

Fiorentzis

Kraemer

et al. 2022

Cancers

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Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite local tumor control, no effective therapy has been found to prevent metastasis, resulting in a high mortality rate. In the present study, we evaluated the anti-tumor potential of non-selective ß-blockers in 3D tumor spheroids grown from UM cell lines. Of the various ß-blockers tested, carvedilol and its enantiomers were most potent in decreasing the viability of Mel270 spheroids. Carvedilol at a concentration of 10–50 µM significantly elicited cytotoxicity and induced apoptosis in spheroid cells. In result, carvedilol inhibited tumor spheroid growth and compactness, and furthermore prevented the long-term survival and repopulation of spreading spheroid cells. The drug sensitivity of the different spheroids grown from Mel270, 92-1, UPMD2, or UPMM3 cell lines was dependent on 3D morphology rather than on high-risk cytogenetic profile or adrenergic receptor expression levels. In fact, the monosomy-3-containing UPMM3 cell line was most responsive to carvedilol treatment compared to the other cell lines. The concurrent treatment of UPMM3 spheroids with carvedilol and 5 or 10 Gy irradiation revealed additive cytotoxic effects that provided tumor control. Collectively, our data demonstrate the anti-tumor properties of carvedilol and its enantiomers, which may serve as candidates for the co-adjuvant therapy of UM.

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Section: Discussioncontrasting

confidence: 48%

The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation

Farhoumand

Fiorentzis

Kraemer

et al. 2022

Cancers

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“…The latter cell type was seen particularly in those mUM that had undergone necrosis and were associated with a desmoplastic reaction ( Figure 6 ). Plasma and CD20+ B-cells have been described in primary UM, albeit as focal aggregates in small quantities, and in some cases associated with necrosis [ 26 , 48 , 49 , 50 ]. Our observations may thus explain the relatively poor responses to trialled adoptive transfer of autologous TIL-based therapies in patients with mUM [ 51 ] and emphasise the urgent need to refine T-cell therapy in this setting [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Krishna

Acha-Sagredo

Sabat-Pośpiech

et al. 2020

Cancers

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Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an “immunoscore” (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver; intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p < 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases; LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions.

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“…In contrast to our data, Moschos et al and Hussain et al suggested an increase in radioresistance based on a thorough ATM-related DNA repair. Further analysis should be done to check the role of ATM in the radiation response of cancer and nonmalignant cell lines [20,62].…”

Section: Discussionmentioning

confidence: 99%

Tumor-specific radiosensitizing effect of the ATM inhibitor AZD0156 in melanoma cells with low toxicity to healthy fibroblasts

et al. 2022

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Purpose Despite new treatment options, melanoma continues to have an unfavorable prognosis. DNA damage response (DDR) inhibitors are a promising drug class, especially in combination with chemotherapy (CT) or radiotherapy (RT). Manipulating DNA damage repair during RT is an opportunity to exploit the genomic instability of cancer cells and may lead to radiosensitizing effects in tumors that could improve cancer therapy. Methods A panel of melanoma-derived cell lines of different origin were used to investigate toxicity-related clonogenic survival, cell death, and cell cycle distribution after treatment with a kinase inhibitor (KI) against ATM (AZD0156) or ATR (VE-822, berzosertib), irradiation with 2 Gy, or a combination of KI plus ionizing radiation (IR). Two fibroblast cell lines generated from healthy skin tissue were used as controls. Results Clonogenic survival indicated a clear radiosensitizing effect of the ATM inhibitor (ATMi) AZD0156 in all melanoma cells in a synergistic manner, but not in healthy tissue fibroblasts. In contrast, the ATR inhibitor (ATRi) VE-822 led to additive enhancement of IR-related toxicity in most of the melanoma cells. Both inhibitors mainly increased cell death induction in combination with IR. In healthy fibroblasts, VE-822 plus IR led to higher cell death rates compared to AZD0156. A significant G2/M block was particularly induced in cancer cells when combining AZD0156 with IR. Conclusion ATMi, in contrast to ATRi, resulted in synergistic radiosensitization regarding colony formation in melanoma cancer cells, while healthy tissue fibroblasts were merely affected with respect to cell death induction. In connection with an increased number of melanoma cells in the G2/M phase after ATMi plus IR treatment, ATMi seems to be superior to ATRi in melanoma cancer cell treatments when combined with RT.

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Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons

Cited by 10 publications

References 30 publications

The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation

The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

Tumor-specific radiosensitizing effect of the ATM inhibitor AZD0156 in melanoma cells with low toxicity to healthy fibroblasts

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