PARP-1 depletion in combination with carbon ion exposure significantly reduces MMPs activity and overall increases TIMPs expression in cultured HeLa cells

Ghorai, Atanu; Sarma, Asitikantha; Chowdhury, Priyanka; Ghosh, Utpal

doi:10.1186/s13014-016-0703-x

Cited by 18 publications

(21 citation statements)

References 62 publications

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“…PARP-1 binds to SSBs and catalyzes the polymerization of ADP-ribose (PARylation), resulting in the production of polymers of ADP-ribose (PAR). We have reported that the combination of depletion of PARP-1 and C-ion exposure sensitizes HeLa cell and induces apoptosis to a greater extent than C-ion exposure alone [32].…”

Section: Introductionmentioning

confidence: 92%

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Césaire

Ghosh

Austry

et al. 2019

Journal of Bone Oncology

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Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as RAD50, SMARCA2 and NBN . This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation.

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Section: Introductionmentioning

confidence: 92%

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Césaire

Ghosh

Austry

et al. 2019

Journal of Bone Oncology

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“…For carbon ion irradiation, multiple in vitro studies have shown that the use of a PARP inhibitor can sensitize cancer cells to carbon ion irradiation (Table 3) (97,98,212). Interestingly, some of these studies showed that PARP inhibition has a higher radiosensitizing effect in combination with carbon ion radiation compared to photon irradiation (97,98,101). Overall, combining particle radiation with PARP inhibition shows very promising results concerning radiosensitization.…”

Section: Inhibition Of Parpmentioning

confidence: 99%

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance

et al. 2020

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Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors.

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“…Cells were maintained in Radiation Biology Laboratory at IUAC, New Delhi. The irradiation of cells was done using heavy ion irradiation facility ASPIRE, where the dosimetry is done using silicon surface barrier detectors [ 39 , 40 ]. We have used 12 C beam with 85MeV (equivalent to 7.08 MeV/nucleon) energy from the accelerator.…”

Section: Methodsmentioning

confidence: 99%

Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation

2018

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High linear energy transfer (LET) radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator. PNKP (polynucleotide kinase/phosphatase) is an enzyme which plays important role in the non-homologous end joining (NHEJ) DNA repair pathway. It is expected that inhibition of PNKP activity may enhance the efficacy of the charged particle irradiation in the radioresistant prostate cancer cell line PC-3. To test this hypothesis, we investigated cellular radiosensitivity by clonogenic cell survival assay in PC-3 cells.12Carbon ion beam of62 MeVenergy (equivalent 5.16 MeV/nucleon) and with an entrance LET of 287 kev/μm was used for the present study. Apoptotic parameters such as nuclear fragmentation and caspase-3 activity were measured by DAPI staining, nuclear ladder assay and colorimetric caspase-3method. Cell cycle arrest was determined by FACS analysis. Cell death was enhanced when carbon ion irradiation is combined with PNKPi (PNKP inhibitor) to treat cells as compared to that seen for PNKPi untreated cells. A low concentration (10μM) of PNKPi effectively radiosensitized the PC-3 cells in terms of reduction of dose in achieving the same survival fraction. PC-3 cells underwent significant apoptosis and cell cycle arrest too was enhanced at G2/M phase when carbon ion irradiation was combined with PNKPi treatment. Our findings suggest that combined treatment of carbon ion irradiation and PNKP inhibition could enhance cellular radiosensitivity in a radioresistant prostate cancer cell line PC-3. The synergistic effect of PNKPi and carbon ion irradiation could be used as a promising method for carbon-ion therapy in radioresistant cells.

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PARP-1 depletion in combination with carbon ion exposure significantly reduces MMPs activity and overall increases TIMPs expression in cultured HeLa cells

Cited by 18 publications

References 62 publications

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance

Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation

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