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    Radiobiology Final Version

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    Andres Leiva Genre
    Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation. The study found that: 1) Pretreating radioresistant PC-3 prostate cancer cells with the PNKP inhibitor A12B4C3 prior to carbon ion beam radiation significantly reduced the radiation dose required to kill 10% of cells (D10). 2) Combining PNKP inhibition and carbon ion beam radiation enhanced cell death, cell cycle arrest, and apoptosis compared to radiation alone. 3) PNKP inhibition at a concentration of 10 μM achieved good synergy with carbon ion beam treatment with minimal toxicity, suggesting it could help lower radiation doses required for prostate cancer treatment.

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    Radiobiology Final Version

    Uploaded by

    Andres Leiva Genre
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    Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation. The study found that: 1) Pretreating radioresistant PC-3 prostate cancer cells with the PNKP inhibitor A12B4C3 prior to carbon ion beam radiation significantly reduced the radiation dose required to kill 10% of cells (D10). 2) Combining PNKP inhibition and carbon ion beam radiation enhanced cell death, cell cycle arrest, and apoptosis compared to radiation alone. 3) PNKP inhibition at a concentration of 10 μM achieved good synergy with carbon ion beam treatment with minimal toxicity, suggesting it could help lower radiation doses required for prostate cancer treatment.

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    Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation. The study found that: 1) Pretreating radioresistant PC-3 prostate cancer cells with the PNKP inhibitor A12B4C3 prior to carbon ion beam radiation significantly reduced the radiation dose required to kill 10% of cells (D10). 2) Combining PNKP inhibition and carbon ion beam radiation enhanced cell death, cell cycle arrest, and apoptosis compared to radiation alone. 3) PNKP inhibition at a concentration of 10 μM achieved good synergy with carbon ion beam treatment with minimal toxicity, suggesting it could help lower radiation doses required for prostate cancer treatment.

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    18 views12 pages

    Radiobiology Final Version

    Uploaded by

    Andres Leiva Genre
    Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation. The study found that: 1) Pretreating radioresistant PC-3 prostate cancer cells with the PNKP inhibitor A12B4C3 prior to carbon ion beam radiation significantly reduced the radiation dose required to kill 10% of cells (D10). 2) Combining PNKP inhibition and carbon ion beam radiation enhanced cell death, cell cycle arrest, and apoptosis compared to radiation alone. 3) PNKP inhibition at a concentration of 10 μM achieved good synergy with carbon ion beam treatment with minimal toxicity, suggesting it could help lower radiation doses required for prostate cancer treatment.

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    of 12

    TARGETING DNA REPAIR WITH PNKP

    INHIBITION SENSITIZES
    RADIORESISTANT PROSTATE CANCER
    CELLS WITH HIGH LET RADIATION

    RADIOTHERAPY EXAM

    Student: ANDRÉS LEIVA GENRE


    Caen, France
    Date: 23.11.2022
    Professor: Haghdoost Siamak

    2022 Radiotherapy 1
    CONTENT

    Background

    Methods

    Results

    Discussion

    Conclusion
    2
    HIGH LET Carbon ions therapy

    PC-3 cells They have a defective p53 compound with


    RADIORES ISTANT
    TUMORS overexpressed Bcl-2 which makes it antiapoptotic and
    resistant to cell death.

    DNA REPAIR PNKP (Polynucleotide Kinase Phosphatase)

    RADIOMODUL ATOR A12B4C3

    BACKGROUND
    2022 Radiotherapy 3
    METHODS

    SCHEMATIC WORKFLOW FOR THE EXPERIMENTS


    2022 Radiotherapy 4
    METHODS

    PC-3 Cells 24h prior treatment 2)


    62 MeV Carbon ion beam 𝑆 𝐹 = 𝑒 (−𝛼𝐷−𝛽𝐷
    with PNKP inhibitor
    - 287 keV/µm LET
    A12B4C3 2-4h prior
    irradiation

    𝐷10 (𝑤\out 𝑑𝑟𝑢𝑔)


    SER = 24 hours after cell
    𝐷10 (𝑤𝑖𝑡ℎ 𝑑𝑟𝑢𝑔) Plays a central role in 24 hours after cell
    irradiation execution-phase of cell irradiation
    Reduction in Dose (%) = 𝐷10 (𝑤\out 𝑑𝑟𝑢𝑔) +
    1 apoptosis
    𝑆𝐸𝑅

    2022 Radiotherapy 5
    RESULTS

    SURVIVING FRACTION OF PC-3


    CELLS FOR DIFFERENT A12B4C3
    CONCENTRATION

    10 µM of A12B4C3 (PNKPi) permits a very


    good synergy with C-12 ion treatment while
    not showing a high level of toxicity in cells

    2022 Radiotherapy 6
    RESULTS

    𝐷10 (𝑤\out 𝑑𝑟𝑢𝑔) 1


    SER = Reduction in Dose (%) = 𝐷10 (𝑤\out 𝑑𝑟𝑢𝑔) +
    𝐷10 (𝑤𝑖𝑡ℎ 𝑑𝑟𝑢𝑔) 𝑆𝐸𝑅

    2022 Radiotherapy 7
    RESULTS

    EFFECTS ON CELL MORPHOLOGY,


    POPULATION AND PROLIFERATION

    • Noticeable change in cell


    morphology
    • Population of cells is reduced
    • Decrease in cell proliferation

    20XX Radiotherapy 8
    RESULTS

    Apoptosis Enhancement Increase of cell cycle arrest at G2/M phase

    20XX Pitch Deck 9


    DISCUSSION

    Use of PNKPi SF at D10 with C-ion


    radiosensitizer beam

    Significant sensitizer 10µM A12B4C3’s


    enhancement at D10 concentration

    PC-3 cells underwent p53-


    independent apoptosis

    2022 Radiotherapy 10
    CONCLUSION

    • PNKP inhibition plus heavy-ion therapy


    enhance cell death and stop recurrence
    in radioresistant prostate cancer cells
    • Efficiency increment in C-12 ion therapy
    • Low A12B4C3’s concentration enable
    lowering doses

    2022 Radiotherapy 11
    THANK YOU!

    2022 Radiotherapy 12

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