Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer

Lee, Yu Chieh; Lee, Chii Hong; Tsai, Hsiang Ping; An, Herng Wei; Lee, Chi-Ming; Wu, Jen Chine; Chen, Chien Shu; Huang, Shu‐Mei; Hwang, Jiann Loung; Cheng, Kur Ta; Leiw, Phui Ly; Chen, Chi Long; Lin, Chun Mao

doi:10.1371/journal.pone.0132579

Cited by 32 publications

(27 citation statements)

References 48 publications

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“…Camptothecin, the first small molecule targeting Top I for the treatment of advanced digestive carcinoma in clinical2331, which stabilizes the DNA cleavable complex to block the transient breaking and rejoining of DNA173233 and has been used as the Top I poison for the treatment of many digestive solid tumors widely34, was served as the positive control. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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Crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity. However, the specific alkaloids responsible for the pharmacodynamic activity and their targets still remain elusive. In this context, we strived to combine affinity ultrafiltration with topoisomerase I (Top I) as a target enzyme aiming to fish out specific bioactive AAs from Lycoris radiata. 11 AAs from Lycoris radiata were thus screened out, among which hippeastrine (peak 5) with the highest Enrichment factor (EF) against Top I exhibited good dose-dependent inhibition with IC50 at 7.25 ± 0.20 μg/mL comparable to camptothecin (positive control) at 6.72 ± 0.23 μg/mL. The molecular docking simulation further indicated the inhibitory mechanism between Top I and hippeastrine. The in vitro antiproliferation assays finally revealed that hippeastrine strongly inhibited the proliferation of HT-29 and Hep G2 cells in an intuitive dose-dependent manner with the IC50 values at 3.98 ± 0.29 μg/mL and 11.85 ± 0.20 μg/mL, respectively, and also induced significant cellular morphological changes, which further validated our screening method and the potent antineoplastic effects. Collectively, these results suggested that hippeastrine could be a very promising anticancer candidate for the therapy of cancer in the near future.

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Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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“…Numerous researches have reported that TOP1 is over-expression in various kinds of human tumors [38–41]. Increasing evidences demonstrate that TOP1 protein level, gene copy number, and mRNA expression are significantly correlated to unfavorable prognosis in most types of tumor [26, 42, 43]. However, the prognostic effect of TOP 1 in some tumors was controversial.…”

Section: Discussionmentioning

confidence: 99%

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan–Meier plotter

et al. 2017

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DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan–Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients.

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“…Camptothecin is a topoisomerase I inhibitor acting to induce DNA breaks. The cancer cells over‐expressed XRCC1 resist to camptothecin and the XRCC1 deficient cells are sensitive to camptothecin . Therefore, these data suggest XRCC1 would be an important target for BBR to function in DNA repair.…”

Section: Resultsmentioning

confidence: 86%

“…The cancer cells over-expressed XRCC1 resist to camptothecin and the XRCC1 deficient cells are sensitive to camptothecin. 35,36 Therefore, these data suggest XRCC1 would be an important target for BBR to function in DNA repair. We also tested the synergistic effects between BBR and HU, as well as between BBR and olaparib.…”

Section: Berberine Sensitizes Mda-mb-231 Cells To Cisplatin Camptomentioning

confidence: 84%

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

Gao

Wang

et al. 2019

J Cellular Molecular Medi

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Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti‐microbial, anti‐protozoal, anti‐diarrhoeal activities. Berberine interacts with DNA and displays anti‐cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti‐tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA‐MB‐231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down‐regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1‐mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.

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Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer

Cited by 32 publications

References 48 publications

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan–Meier plotter

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

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