Acridine derivatives as inhibitors/poisons of topoisomerase II

Kožurková, Mária

doi:10.1002/jat.4238

Cited by 10 publications

(9 citation statements)

References 43 publications

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“…Acridine derivatives are an attractive class of anticancer agents that generally operate by inhibiting Topo II. m‐AMSA is the first significant drug that was approved for clinical application as a Topo II poison [44] …”

Section: Resultsmentioning

confidence: 99%

“…m-AMSA is the first significant drug that was approved for clinical application as a Topo II poison. [44] Two acridine derivatives 30 and 32 as well as m-AMSA were tested for their human topoisomerase IIα inhibitory activity using the human topoisomerase II relaxation assay. The compounds were tested at the concentration range of 0.1-100 μM to determine IC 50 values.…”

Section: Human Topoisomerase Iiα Relaxation Assaymentioning

confidence: 99%

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Acridine/Acridone–Carborane Conjugates as Strong DNA‐Binding Agents with Anticancer Potential

et al. 2023

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Synthesis of acridine derivatives that act as DNA-targeting anticancer agents is an evolving field and has resulted in the introduction of several drugs into clinical trials. Carboranes can be of importance in designing biologically active compounds due to their specific properties. Therefore, a series of novel acridine analogs modified with carborane clusters were synthesized. The DNA-binding ability of these analogs was evaluated on calf thymus DNA (ct-DNA). Results of these analyses showed that 9-[(1,7-dicarba-closo-dodecaborane-1-yl)propylamino]acridine (30) interacted strongly with ct-DNA, indicating its ability to intercalate into DNA, whereas 9-[(1,7dicarba-closo-dodecaborane-1-yl)propanamido]acridine (29) changed the B-form of ct-DNA to the Z form. Compound 30 demonstrated cytotoxicity, was able to inhibit cell proliferation, arrest the cell cycle in the S phase in the HeLa cancer cell line, and induced the production of reactive oxygen species (ROS). In addition, it was specifically localized in lysosomes and was a weak inhibitor of Topo IIα.

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Section: Resultsmentioning

confidence: 99%

Section: Human Topoisomerase Iiα Relaxation Assaymentioning

confidence: 99%

Acridine/Acridone–Carborane Conjugates as Strong DNA‐Binding Agents with Anticancer Potential

et al. 2023

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“…23 However, the research on TOP II inhibitors still attracts much attention. [24][25][26][27] TOP IIα and TOP IIβ are two subclasses of TOP II. TOP IIα is related to cancer cell growth, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

et al. 2023

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BackgroundCastration‐resistant prostate cancer (CRPC) is refractory to hormone treatment and the therapeutic options are continuously advancing. This study aims to discover the anti‐CRPC effects and underlying mechanisms of small‐molecule compounds targeting topoisomerase (TOP) II and cellular components of DNA damage repair.MethodsCell proliferation was determined in CRPC PC‐3 and DU‐145 cells using anchorage‐dependent colony formation, sulforhodamine B assay and flow cytometric analysis of CFSE staining. Flow cytometric analyses of propidium iodide staining and JC‐1 staining were used to examine the population of cell‐cycle phases and mitochondrial membrane potential, respectively. Nuclear extraction was performed to detect the nuclear localization of cellular components in DNA repair pathways. Protein expressions were determined using Western blot analysis.ResultsA series of azathioxanthone‐based derivatives were synthesized and examined for bioactivities in which WC‐A13, WC‐A14, WC‐A15, and WC‐A16 displayed potent anti‐CRPC activities in both PC‐3 and DU‐145 cell models. These WC‐A compounds selectively downregulated both TOP IIα and TOP IIβ but not TOP I protein expression. WC‐A13, WC‐A14, and WC‐A15 were more potent than WC‐A16 on TOP II inhibition, mitochondrial dysfunction, and induction of caspase cascades indicating the key role of amine‐containing side chain of the compounds in determining anti‐CRPC activities. Furthermore, WC‐A compounds induced an increase of γH2AX and activated ATR‐Chk1 and ATM‐Chk2 signaling pathways. P21 protein expression was also upregulated by WC‐A compounds in which WC‐A16 showed the least activity. Notably, WC‐A compounds exhibited different regulation on Rad51, a major protein in homologous recombination of DNA in double‐stranded break repair. WC‐A13, WC‐A14, and WC‐A15 inhibited, whereas WC‐A16 induced, the nuclear translocation of Rad51.ConclusionThe data suggest that WC‐A compounds exhibit anti‐CRPC effects through the inhibition of TOP II activities, leading to mitochondrial stress‐involved caspase activation and apoptosis. Moreover, WC‐A13, WC‐A14, and WC‐A15 but not WC‐A16 display inhibitory activities of Rad51‐mediated DNA repair pathway which may increase apoptotic effect of CRPC cells.

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“…Acridine-based agents represent a family of heterocyclic compounds which are currently undergoing significant research because of their potential anticancer activity. The pleiotropic mechanism of the antiproliferative effect of acridine derivatives, including topoisomerase II inhibition [ 57 ], cell cycle arrest in S phase [ 58 ] and G2/M phase [ 59 ], tubulin polymerization inhibition [ 60 ], DNA damage [ 61 ] and apoptosis induction [ 58 ] have been documented.…”

Section: Discussionmentioning

confidence: 99%

Chalcone-Acridine Hybrid Suppresses Melanoma Cell Progression via G2/M Cell Cycle Arrest, DNA Damage, Apoptosis, and Modulation of MAP Kinases Activity

Gazdova

Michalková

Kello

et al. 2022

IJMS

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This study was focused on investigating the antiproliferative effects of chalcone hybrids in melanoma cancer cells. Among seven chalcone hybrids, the chalcone-acridine hybrid 1C was the most potent and was selected for further antiproliferative mechanism studies. This in vitro study revealed the potent antiproliferative effect of 1C via cell cycle arrest and apoptosis induction. Cell cycle arrest at the G2/M phase was associated with modulation of expression or phosphorylation of specific cell cycle-associated proteins (cyclin B1, p21, and ChK1), tubulins, as well as with the activation of the DNA damage response pathway. Chalcone 1C also induced apoptosis accompanied by mitochondrial dysfunction evidenced by a decrease in mitochondrial membrane potential, increase in Bax/Bcl-xL ratio and cytochrome c release followed by caspase 3/7 activation. In addition, increased phosphorylation of MAP kinases (Erk1/2, p38 and JNK) was observed in chalcone 1C-treated melanoma cells. The strong antiproliferative activities of this chalcone-acridine hybrid suggest that it may be useful as an antimelanoma agent in humans.

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Acridine derivatives as inhibitors/poisons of topoisomerase II

Cited by 10 publications

References 43 publications

Acridine/Acridone–Carborane Conjugates as Strong DNA‐Binding Agents with Anticancer Potential

Acridine/Acridone–Carborane Conjugates as Strong DNA‐Binding Agents with Anticancer Potential

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

Chalcone-Acridine Hybrid Suppresses Melanoma Cell Progression via G2/M Cell Cycle Arrest, DNA Damage, Apoptosis, and Modulation of MAP Kinases Activity

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