Enhancement of Radiosensitivity by Eurycomalactone in Human NSCLC Cells Through G<sub>2</sub>/M Cell Cycle Arrest and Delayed DNA Double-Strand Break Repair

Dukaew, Nahathai; Konishi, Teruaki; Chairatvit, Kongthawat; Autsavapromporn, Narongchai; Soonthornchareonnon, Noppamas; Wongnoppavich, Ariyaphong

doi:10.3727/096504019x15736439848765

Cited by 20 publications

(19 citation statements)

References 30 publications

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“…Understanding the underlying mechanisms by which DNA damage is repaired in cancer cells post IR treatment would facilitate overcoming RR 159 . For instance, eurycomalactone, an active quassinoid isolated from Eurycoma longifolia Jack, markedly delayed the repair of radiation-induced DSBs in non-small-cell lung cancer (NSCLC) cells 160 . Koval et al 157 reported that a protective system could be activated among cancer cells in response to IR, leading to increased resistance to subsequent exposure to IR, and moreover, chronic exposure to γ-rays increased the expression of the mus210, mus219, and mus309 genes, even after 56 days, in Canton-S flies.…”

Section: Signaling Pathways Of Ddr and Repairmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

680

457

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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Section: Signaling Pathways Of Ddr and Repairmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

680

457

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“…Meanwhile, the damage that occurs during G2/M can more easily cause premature entry into mitosis, which can lead to a higher possibility of passing incorrect genomic information to the next generation, or even cause mitotic catastrophe directly (43). Eurycomalactone, an active quassinoid isolated from Eurycoma longifolia, has been shown to sensitize non-small cell lung cancer cells to X-rays through a G2/M block (44). Further studies have focused on the G2/M arrest after receiving radiation.…”

Section: Cell Cycle Distributionmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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“…However, the mechanisms underlying the strong cytotoxicity of ECL against human NSCLC cells have not been investigated. Our previous study reported that ECL efficiently sensitized X-ray-induced apoptosis of NSCLC A549 and COR-L23 cells by inducing cell cycle arrest at the G2/M phase and inhibiting the repair of radiation-induced DNA double-strand breaks (21). Notably, ECL was also reported to inhibit the NF-κB activity in TNF-α-activated 293/NF-κB-luc cells, a stable cell line containing an NF-κB driven luciferase reporter gene (22).…”

Section: Inactivation Of Akt/nf-κb Signaling By Eurycomalactone Decrementioning

confidence: 99%

Inactivation of AKT/NF‑κB signaling by eurycomalactone decreases human NSCLC cell viability and improves the chemosensitivity to cisplatin

et al. 2020

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The high activation of protein kinase B (AKT)/nuclear factor-κB (NF-κB) signaling has often been associated with the induction of non-small cell lung cancer (NSCLC) cell survival and resistance to cisplatin, which is one of the most widely used chemotherapeutic drugs in the treatment of NSCLC. The inhibition of AKT/NF-κB can potentially be used as a molecular target for cancer therapy. Eurycomalactone (ECL), a quassinoid from Eurycoma longifolia Jack, has previously been revealed to exhibit strong cytotoxic activity against the human NSCLC A549 cell line, and can inhibit NF-κB activity in TNF-α-activated 293 cells stably transfected with an NF-κB luciferase reporter. The present study was the first to investigate whether ECL inhibits the activation of AKT/NF-κB signaling, induces apoptosis and enhances chemosensitivity to cisplatin in human NSCLC cells. The anticancer activity of ECL was evaluated in two NSCLC cell lines, A549 and Calu-1. ECL decreased the viability and colony formation ability of both cell lines by inducing cell cycle arrest and apoptosis through the activation of pro-apoptotic caspase-3 and poly (ADP-ribose) polymerase, as well as the reduction of anti-apoptotic proteins Bcl-xL and survivin. In addition, ECL treatment suppressed the levels of AKT (phospho Ser473) and NF-κB (phospho Ser536). Notably, ECL significantly enhanced cisplatin sensitivity in both assessed NSCLC cell lines. The combination treatment of cisplatin and ECL promoted cell apoptosis more effectively than cisplatin alone, as revealed by the increased cleaved caspase-3, but decreased Bcl-xL and survivin levels. Exposure to cisplatin alone induced the levels of phosphorylated-AKT and phosphorylated-NF-κB, whereas co-treatment with ECL inhibited the cisplatin-induced phosphorylation of AKT and NF-κB, leading to an increased sensitization effect on cisplatin-induced apoptosis. In conclusion, ECL exhibited an anticancer effect and sensitized NSCLC cells to cisplatin through the inactivation of AKT/NF-κB signaling. This finding provides a rationale for the combined use of chemotherapy drugs with ECL to improve their efficacy in NSCLC treatment.

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Enhancement of Radiosensitivity by Eurycomalactone in Human NSCLC Cells Through G₂/M Cell Cycle Arrest and Delayed DNA Double-Strand Break Repair

Cited by 20 publications

References 30 publications

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Inactivation of AKT/NF‑κB signaling by eurycomalactone decreases human NSCLC cell viability and improves the chemosensitivity to cisplatin

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Enhancement of Radiosensitivity by Eurycomalactone in Human NSCLC Cells Through G2/M Cell Cycle Arrest and Delayed DNA Double-Strand Break Repair

Cited by 20 publications

References 30 publications

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Inactivation of AKT/NF‑κB signaling by eurycomalactone decreases human NSCLC cell viability and improves the chemosensitivity to cisplatin

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Product

Resources

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Enhancement of Radiosensitivity by Eurycomalactone in Human NSCLC Cells Through G₂/M Cell Cycle Arrest and Delayed DNA Double-Strand Break Repair