Journey of anthraquinones as anticancer agents – a systematic review of recent literature

Malik, M. Shaheer; Alsantali, Reem I.; Jassas, Rabab S.; Alsimaree, Abdulrahman A.; Syed, Rabbani; Alsharif, Meshari A.; Kalpana, Kulkarni; Morad, Moataz; Althagafi, Ismail; Ahmed, Saleh A.

doi:10.1039/d1ra05686g

Cited by 79 publications

(65 citation statements)

References 171 publications

(213 reference statements)

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“…Considering the metabolites identified in the leaf and SCC extracts, the results obtained from this study are consistent with other reports of the presence of terpenoid, phenolic, flavonoid, and quinone compounds in R. nasutus leaves, conferring significant free radical scavenging activity and cancer-inhibitory effects [ 41 , 49 , 50 , 56 , 58 , 59 , 83 , 84 ]. Similar metabolite profiles were observed between the leaf and SCC extracts, with the leaf extract potentially showing greater metabolite accumulation.…”

Section: Discussionsupporting

confidence: 90%

Antioxidant and Anticancer Potential of Bioactive Compounds from Rhinacanthus nasutus Cell Suspension Culture

Songserm

Klanrit

Phetcharaburanin

et al. 2022

Plants

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The potential benefits of natural plant extracts have received attention in recent years, encouraging the development of natural products that effectively treat various diseases. This is the first report on establishing callus and cell suspension cultures of Rhinacanthus nasutus (L.) Kurz. A yellow friable callus was successfully induced from in vitro leaf explants on Murashige and Skoog medium supplemented with 1 mg/L 2,4-dichlorophenoxyacetic acid and 1 mg/L 1-naphthalene acetic acid. A selected friable callus line was used to establish the cell suspension culture with the same medium. The antioxidant assays showed that the leaf- and ethanolic-suspension-cultured cell (SCC) extracts exhibited high antioxidant potential. In addition, the in vitro cytotoxicity revealed by the MTT assay demonstrated potent antiproliferative effects against the oral cancer cell lines ORL-48 and ORL-136 in a dose-dependent manner. Several groups of compounds, including terpenoids, phenolics, flavonoids, quinones, and stilbenes, were identified by UHPLC–QToF–MS, with the same compounds detected in leaf and SCC extracts, including austroinulin, lucidenic acid, esculetin, embelin, and quercetin 3-(2″-p-hydroxybenzoyl-4″-p-coumarylrhamnoside). The present study suggests the value of further investigations for phytochemical production using R. nasutus cell suspension culture.

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Section: Discussionsupporting

confidence: 90%

Antioxidant and Anticancer Potential of Bioactive Compounds from Rhinacanthus nasutus Cell Suspension Culture

Songserm

Klanrit

Phetcharaburanin

et al. 2022

Plants

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“…Anthraquinone derivatives, such as doxorubicin and mitoxantrone analogs are potent anticancer drugs owing to their ability to intercalate DNA to induce damage 29 . However, our earlier studies 28 have shown the ability of our lead compound BW-AQ-101 ( Figure 1 ) derived from rhein to down-regulated MDM2 without the general cytotoxicity by inducing DNA damage.…”

Section: Resultsmentioning

confidence: 99%

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Tripathi

Anifowose

Wen

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Overexpression of ubiquitin ligase MDM2 causes depletion of the p53 tumour-suppressor and thus leads to cancer progression. In recent years, anthraquinone analogs have received significant attention due to their ability to downregulate MDM2, thereby promoting p53-induced apoptosis. Previously, we have developed potent anthraquinone compounds having the ability to upregulate p53 via inhibition of MDM2 in both cell culture and animal models of acute lymphocytic leukaemia. Earlier work was focussed on mechanistic work, pharmacological validation of this class of compounds in animal models, and mapping out structural space that allows for further modification and optimisation. Herein, we describe our work in optimising the substituents on the two phenol hydroxyl groups. It was found that the introduction of an alkylketone moiety led to a potent series of analogs with BW-AQ-350 being the most potent compound yet (IC 50 = 0.19 ± 0.01 µM) which exerts cytotoxicity by inducing MDM2 degradation and p53 upregulation.

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“…Anthraquinones have been recognized as cancer growth inhibitors targeting topoisomerases, telomerase, matrix metalloproteinases, and protein kinase. 29,30 Several drugs containing an anthraquinone scaffold, such as doxorubicin, epirubicin, pixantrone, valrubicin, and MTX, are clinically used to treat various types of cancers. 31 All known telomerase-targeting anthraquinones act as stabilizers of telomeric DNA G4, altering the binding of telomerase enzyme to DNA and blocking telomerase activity in vitro and vivo.…”

Section: Discussionmentioning

confidence: 99%

Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres

Maciejewska

Olszewski

Jurasz

et al. 2022

Preprint

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Telomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered as a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using cellular thermal shift assay. Together with the compound-induced aggregation, human telomerase reverse transcriptase (hTERT) was translocated from the nucleus to the cytoplasm, which suggested compound-mediated inhibition making the enzyme accessible to its natural substrate. Molecular studies confirmed the binding of hit compound with the active site of hTERT. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 cell lines, but not in TERT-negative HUVEC and ALT-positive U2OS cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damages activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in nonsmall cell lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.

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Journey of anthraquinones as anticancer agents – a systematic review of recent literature

Abstract: Anthraquinones are privileged chemical motifs with diverse therapeutic applications, especially in the treatment of cancer. The extensive literature highlights the significance of anthraquinones as potent anticancer agents.

Cited by 79 publications

References 171 publications

Antioxidant and Anticancer Potential of Bioactive Compounds from Rhinacanthus nasutus Cell Suspension Culture

Antioxidant and Anticancer Potential of Bioactive Compounds from Rhinacanthus nasutus Cell Suspension Culture

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres

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