Discovery of a Novel Series of Quinolone and Naphthyridine Derivatives as Potential Topoisomerase I Inhibitors by Scaffold Modification

You, Qidong; Li, Zhiyu; Huang, Chiung-Hua; Yang, Qian; Wang, Xiaojian; Guo, Qinglong; Chen, Xiaoguang; He, Xiao‐Gang; Li, Tsai-Kun; Chern, Ji‐Wang

doi:10.1021/jm900469e

Cited by 67 publications

(25 citation statements)

References 21 publications

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“…To further identify the underlying mechanism, the formation of TOP1cc was studied. The correlation between TOP1cc formation and DNA damage response has been reported in a wide variety of cancer cells when exposed to topoisomerase I inhibitors [27,28]. Moreover, it has been reported that in SN38 (an active metabolite of irinotecan) resistant cancer cell clones, the presence of topoisomerase I mutations did not change the expression level and activity of topoisomerase I, but decrease the TOP1cc associated with a reduction in DSBs when challenged with SN38 [29].…”

Section: Discussionmentioning

confidence: 99%

Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCδ-independent pathway

Hsu

et al. 2012

Biochemical Pharmacology

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Combination therapy, which can optimize killing activity to cancers and minimize drug resistance, is a mainstream therapy against hormone-refractory prostate cancers (HRPCs). Rottlerin, a natural polyphenolic component, synergistically increased PC-3 (a HRPC cell line) apoptosis induced by camptothecin (a topoisomerase I inhibitor). Using siRNA technique to knockdown protein kinase C-δ (PKCδ), the data showed that rottlerin-mediated synergistic effect was PKCδ-independent, although rottlerin has been used as a PKCδ inhibitor. Rottlerin potentiated camptothecin-induced DNA fragmentation at S phase and ATM phosphorylation at Ser1981. The effect was correlated to apoptosis (r2 = 0.9). To detect upstream signals, the data showed that camptothecin acted on and stabilized topoisomerase I-DNA complex, leading to the formation of camptothecin-trapped cleavage complexes (TOP1cc). The effect was potentiated by rottlerin. To determine DNA repair capability, the time-related γH2A.X formation was examined after camptothecin removal. Consequently, rottlerin significantly inhibited camptothecin removal-mediated decline of γH2A.X formation at S phase, indicating the impairment of DNA repair activity in the presence of rottlerin. The combinatory treatment of camptothecin and rottlerin induced conformational change and activation of Bax and formation of truncated Bad, suggesting the contribution of mitochondria stress to apoptosis. In summary, the data suggest that rottlerin-mediated camptothecin sensitization is through the augmented stabilization of TOP1cc, leading to an increase of DNA damage stress and, possibly, an impairment of DNA repair capability. Subsequently, mitochondria-involved apoptosis is triggered through Bax activation and truncated Bad formation. The novel discovery may provide an anticancer approach of combinatory use between rottlerin and camptothecin for the treatment of HRPCs.

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Section: Discussionmentioning

confidence: 99%

Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCδ-independent pathway

Hsu

et al. 2012

Biochemical Pharmacology

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“…Quinolones were shown to possess also antitumor and immunomodulatory activities (Tawfik et al ., 1990; Xia et al ., 2001; Riesbeck, 2002; Dalhoff & Shalit, 2003; Dalhoff, 2005; Drygin et al ., 2009; You et al ., 2009; Chou et al ., 2009; Azema et al ., 2009; George & Pilli, 2013).…”

Section: Introductionmentioning

confidence: 99%

Original Article. Study of the cytotoxic/toxic potential of the novel anticancer selenodiazoloquinolone on fibroblast cells and 3D skin model

Jantová

Topoľská

Janošková

et al. 2016

Interdisciplinary Toxicology

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The new synthetically prepared quinolone derivative 7-ethyl 9-ethyl-6-oxo-6,9-dihydro[1,2,5]selenadiazolo [3,4-h]quinoline-7-carboxylate (E2h) showed in our previous study cytotoxic effects towards tumor cells and immunomodulatory activities on RAW 264.7 cell line murine macrophages. E2h may have a potential use as a novel chemotherapeutic agent with immunomodulatory properties and the ability to induce apoptotic death of cancer cells. The aim of the present study was to examine the antiproliferative/cytotoxic activities of E2h on human non-cancer fibroblast BHNF-1 cells and reconstructed human epidermis EpiDerm™. Further the effects of E2h on tissue structure and morphology were examined. Cytotoxic/toxic studies showed that selenadiazoloquinolone is not toxic on normal human fibroblast cells BHNF-1 and dimensional skin constructs EpiDerm™. Evaluation of morphological changes in EpiDerm™ showed no change in the construction and morphology of skin tissue treated by E2h compared to control.

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“…However, many antitumor fluoroquinolones have been modified from clinical antibacterial fluoroquinolones with regard to the nitrogencontaining ring, such as piperazine, on the 7-position and (or) the 2-position of the fluoroquinolone scaffold [8,9] . In addition, a few modifications of the carboxylic group at the 3-position have been reported [10] . Indeed, it does not seem necessary for an antitumor fluoroquinolone to retain the carboxylic group; fluoroquinolones with a fused heterocyclic ring as an isostere of the carboxylic group showed strong anticancer activity as well as high water solubility [11] .…”

Section: Introductionmentioning

confidence: 99%

Piperonal ciprofloxacin hydrazone induces growth arrest and apoptosis of human hepatocarcinoma SMMC-7721 cells

Shi

Kang

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the cytotoxic effects of piperonal ciprofloxacin hydrazone (QNT4), a novel antibacterial fluoroquinolone derivative, against human hepatocarcinoma SMMC-7721 cells. Methods: Human hepatocarcinoma cells (SMMC-7721), human breast adenocarcinoma cells (MCF-7) and human colon adenocarcinoma cells (HCT-8) were tested. The effects of QNT4 on cell proliferation were examined using MTT assay. Cell apoptosis was determined using Hoechst 33258 fluorescence staining, TUNEL assay and agarose gel electrophoresis. The topoisomerase II activity was measured using agarose gel electrophoresis with the DNA plasmid pBR322 as the substrate. Mitochondrial membrane potential (∆ψm) was measured using a high content screening imaging system. Protein expression of caspase-9, caspase-8, caspase-3, p53, Bcl-2, Bax, and cytochrome c was detected with Western blot analysis. Results: Treatment with QNT4 (0.625-10 μmol/L) potently inhibited the proliferation of the cancer cells in time-and dose-dependent manners (the IC 50 value at 24 h in SMMC-7721 cells, MCF-7 cells and HCT-8 cells was 2.956±0.024, 3.710±0.027, and 3.694±0.030 μmol/L, respectively). Treatment of SMMC-7721 cells with QNT4 (0.2146, 2.964, and 4.600 μmol/L) for 24 h dose-dependently increased the percentage of apoptotic cells, elicited characteristic DNA "ladder" bands, and decreased the mitochondrial membrane potential. QNT4 dose-dependently increased topoisomerase II-mediated DNA breaks while inhibiting DNA relegation, thus keeping the DNA in fragments. Treatment of SMMC-7721 cells with QNT4 significantly increased cytochrome c in the cytosol, and decreased cytochrome c in the mitochondrial compartment. QNT4 (3-7.39 μmol/L) significantly increased the protein expression of p53, Bax, caspase-9, caspase-3, and the cleaved activated forms of caspase-9 and caspase-3 in SMMC-7721 cells. In contrast, the expression of Bcl-2 was decreased, while caspase-8 had no significant change. Conclusion: QNT4 induced the apoptosis of SMMC-7721 cells via inhibiting topoisomerase II activity and modulating mitochondrialdependent pathways.

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Discovery of a Novel Series of Quinolone and Naphthyridine Derivatives as Potential Topoisomerase I Inhibitors by Scaffold Modification

Cited by 67 publications

References 21 publications

Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCδ-independent pathway

Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCδ-independent pathway

Original Article. Study of the cytotoxic/toxic potential of the novel anticancer selenodiazoloquinolone on fibroblast cells and 3D skin model

Piperonal ciprofloxacin hydrazone induces growth arrest and apoptosis of human hepatocarcinoma SMMC-7721 cells

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