Head and neck cancer radiosensitization by the novel poly(ADP‐ribose) polymerase inhibitor GPI‐15427

Khan, Khurram; Araki, Koji; Daiyou, Wang; Li, Guayan; Li, Xin; Zhang, Jie; Xu, Weizheng; Hoover, Randall; Lauter, Susan; O’Malley, Bert W.; Lapidus, Rena G.; Li, Daqing

doi:10.1002/hed.21195

Cited by 66 publications

(43 citation statements)

References 46 publications

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“…[21][22][23][24][25][26][27] In vivo, PARP inhibitors enhance radiation therapy in syngeneic and xenograft models for colon, lung, head and neck, and cervical cancers. 21,[28][29][30][31][32] Olaparib (AZD2281), which targets PARP1 and PARP2, is currently in several phase I and phase II trials for solid tumors as a single agent or in combination with chemotherapy and/or radiotherapy. 33 A phase I study is ongoing for olaparib plus temozolomide in patients with relapsed GBM (http://www.…”

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confidence: 99%

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

et al. 2013

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Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma.

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Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

et al. 2013

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“…For all in vitro experiments, we used 8 mmol/L final concentration in RPMI-1640 full media. For in vivo experiments, the PARPi was administered at a dose of 100 mg/kg as previously described (20).…”

Section: Parp Inhibitormentioning

confidence: 99%

“…Alkaline and neutral comet assays (Trevigen) were performed as previously described (13,15,20) to quantify the DNA damage 48 hours after treatment. Fluorescent images were captured at Â40 magnification using a Nikon 80i coupled with a SPOT2 CCD camera (Diagnostic Instruments) and IPLab 3.71 software (BD Biosciences).…”

Section: Alkaline and Neutral Comet Assaymentioning

confidence: 99%

“…Growth was evaluated for using a soluble tetrazolium salt MTT assay as previously described (15,16,20). Briefly, cells were seeded into 96-well plates and treated.…”

Section: In Vitro Cell Growthmentioning

confidence: 99%

“…We have previously investigated multiple therapeutic targets focused on DNA repair pathways, including the sensitization of cancer cells to chemotherapy and radiotherapy through the molecular disruption of the Mre11, Rad50, and Nbs1 (MRN) complex (15)(16)(17)(18)(19), as well as through poly (ADP-ribose) polymerase (PARP) inhibition (20). The MRN complex, which plays a critical role in the repair of DNA double-strand breaks (DSB), has been recently implicated in telomere maintenance through interaction with the shelterin complex in both hTERT-positive and ALT cancer cells (21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

Lajud

Nagda

Yamashita

et al. 2014

Clinical Cancer Research

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Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).Experimental Design: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.Results: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.Conclusion: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers. Clin Cancer Res; 20(24); 6465-78. Ó2014 AACR.

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Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer

et al. 2019

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Radioresistance is a major hurdle in the treatment of head and neck squamous cell carcinoma ( HNSCC ). Here, we report that concomitant treatment of HNSCC s with radiotherapy and mevalonate pathway inhibitors (statins) may overcome resistance. Proteomic profiling and comparison of radioresistant to radiosensitive HNSCC s revealed differential regulation of the mevalonate biosynthetic pathway. Consistent with this finding, inhibition of the mevalonate pathway by pitavastatin sensitized radioresistant SQ 20B cells to ionizing radiation and reduced their clonogenic potential. Overall, this study reinforces the view that the mevalonate pathway is a promising therapeutic target in radioresistant HNSCC s.

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Head and neck cancer radiosensitization by the novel poly(ADP‐ribose) polymerase inhibitor GPI‐15427

Abstract: Use of the PARP-1 inhibitor GPI-15427 induced significant sensitization to radiotherapy, representing a promising new treatment in the management of HNSCC.

Cited by 66 publications

References 46 publications

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer

Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer

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