Radiosensitization effect of poly(<scp>ADP</scp>‐ribose) polymerase inhibition in cells exposed to low and high liner energy transfer radiation

Hirai, Takahisa; Shirai, Hidenori; Fujimori, Hiroaki; Okayasu, Ryuichi; Sasai, Keisuke; Masutani, Mitsuko

doi:10.1111/j.1349-7006.2012.02268.x

Cited by 59 publications

(52 citation statements)

References 21 publications

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“…As high LET radiation produces complex types of DNA damage, which are a mixture of single strand break and DSB, PARP may be a promising therapeutic target (21)(22)(23). The results of the present study appear to be in accordance with the PARP inhibitor-induced sensitization with high LET radiation (24), and indicate PARP inhibition may be a potential target for heavy ion radiation therapy.…”

Section: Discussionsupporting

confidence: 77%

Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells

Sunada¹,

Cartwright²,

Hirakawa³

et al. 2017

Oncology Letters

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Abstract. Spread-out Bragg peak (SOBP) C ions have been used clinically in charged particle radiation therapy for years. An SOBP beam consists of various monoenergetic Bragg peaks; however, the biological effect of irradiation with an SOBP beam track has not been well-studied. In order to determine the clinically prospective molecular targets, radiosensitivity to the beam track in DNA repair deficient cell lines was investigated. A total of four distinct Chinese hamster ovary (CHO) cell lines, including CHO10B2 (wild-type), V3 (protein kinase DNA-activated catalytic polypeptide deficient), 51D1 (RAD51 paralog D deficient) and PADR9 [poly(ADP-ribose) polymerase (PARP) deficient], were irradiated with gamma-rays, C ions (290 MeV/n) and Fe ions (500 MeV/n), in order to compare cellular lethality. An OptiCell™ culture system was used to evaluate the lethality at distinct depths of SOBP C ions. Relative biological effectiveness (RBE) values of C ions (linear energy transfer (LET), 13 and 70 keV/µm) and Fe ions (LET, 200 keV/µm) were calculated from cell survival using colony formation assay with standard cell dishes. All cell lines exhibited similar sensitivity to 70 keV/µm C ions and 200 keV/ µm Fe ions. Furthermore, V3 cells did not exhibit increased sensitivity to high LET C ions and Fe ions, compared with low LET gamma-rays and C ions, and 51D1 cells irradiated with 13 keV/µm C ions exhibited relatively high RBE values among the tested cell lines. Conversely, PADR9 cells exhibited low RBE values for 13 keV/µm C ions and high RBE values for 70 keV/µm C ions. Obtained using the OptiCell system, the survival fractions in the SOBP region were uniform for wild-type and PADR9 cells. Conversely, V3 and 51D1 cells exhibited decreased cell death in the distal region of the SOBP. These results indicated that PARP is a more effective target for clinical beam therapy, compared with the non-homologous end joining repair and homologous recombination repair pathways. PARP deficiency may be an optimal target for C ion therapy and the results of the present study may contribute to the development of a more effective heavy ion radiation therapy. IntroductionHeavy ion radiation therapy began in the 1970s in the USA as a more efficient radiation therapy compared with classical X-ray therapy (1,2). Heavy ion therapy is gaining prevalence, and has been increasingly utilized in Japan, China, Germany and Italy (1,2). Heavy ions exhibit three advantageous cancer cell killing characteristics when compared with X-rays. Heavy ions exhibit a more efficient dose distribution in cancer tissues due to the Bragg peak. The phenomenon allows for the majority of the dose to be deposited within the cancer tissues, avoiding unnecessary radiation exposure to normal tissues. In addition, heavy ions form complex DNA lesions within the cell due to the large amount of energy deposited during particle/DNA interactions. Heavy ions are able to produce more complex DNA lesions compared with X-rays and gamma-rays (1,2). Complex DNA damage lesions are more diff...

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Section: Discussionsupporting

confidence: 77%

Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells

Sunada¹,

Cartwright²,

Hirakawa³

et al. 2017

Oncology Letters

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“…PARP1 promotes BER and single-strand break repair (SSBR), and PARP inhibitors, by blocking BER, lead to an increase of collapsed replication forks generating DSBs [262]. Radiosensitization of MiaPaCa-2 cells with olaparib (AZD2281) alone has been reported [263]. Similarly, the same group of researchers have also shown that the combined inhibition of Wee1 tyrosine kinase using a small molecule inhibitor AZD1775 and PARP1 inhibitor olaparib radiosensitizes AsPC-1 and MiaPaCa-2 PC cells significantly.…”

Section: Promising Molecular Targeting Agents As Radiosensitizers mentioning

confidence: 99%

Biological determinants of radioresistance and their remediation in pancreatic cancer

Seshacharyulu

Baine

Souchek

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy.

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“…Focused-beam X-ray radiation produces localized double-stranded DNA breaks and thus would be expected to render cells more sensitive to PARP inhibition (19, 20). Olaparib has been shown to enhance the effect of radiation in both BRCA2-proficient and deficient prostate cancer cells (21).…”

Section: Introductionmentioning

confidence: 99%

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

Ven

Tangutoori

Baldwin

et al. 2017

Molecular Cancer Therapeutics

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The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral Olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13 week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, this data suggests that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions.

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Radiosensitization effect of poly(ADP‐ribose) polymerase inhibition in cells exposed to low and high liner energy transfer radiation

Cited by 59 publications

References 21 publications

Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells

Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells

Biological determinants of radioresistance and their remediation in pancreatic cancer

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

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