Selective <i>in vitro</i> anti-cancer activity of non-alkylating minor groove binders

Nichol, Ryan J O; Khalaf, Abedawn I.; Sooda, Kartheek; Hussain, Omar; Griffiths, Hollie B. S.; Phillips, Roger M.; Javid, Farideh A.; Suckling, Colin J.; Allison, Simon J.; Scott, Fraser J.

doi:10.1039/c9md00268e

Cited by 12 publications

(8 citation statements)

References 18 publications

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“…Ptaquiloside (1) was less active against the noncancer ARPE-19 cell line (IC 50 > 100 µM) compared to all 4 cancer cell lines tested, with 1 being 4.5-fold more active toward the HCT116 colorectal cancer cell line. The selectivity index (SI), defined as the IC 50 for ARPE-19 cells divided by the IC 50 for HCT116 cells was > 4.5, and this compares to a previously reported cancer cell selectivity index of~1.9-2 for the clinically approved platinate, cisplatin, against the same cancer/noncancer cell line pair [9,10] (Fig. 8S, Supporting Information).…”

Section: Resultssupporting

confidence: 58%

An Efficient Method for the Isolation of Toxins from Pteridium aquilinum and Evaluation of Ptaquiloside Against Cancer and Non-cancer Cells

et al. 2021

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The common fern, bracken (Pteridium aquilinum), is well known for its toxic effects on livestock due principally to the carcinogenic constituent ptaquiloside (1), although other toxins are present including the cyanogenic glycoside, prunasin (2). Here, we report an improved and relatively “green” process for the isolation of 1 and 2 from fresh bracken fronds and the evaluation of 1 for cytotoxicity against several cancer cell lines. The results indicate that 1 displays selective toxicity against cancer cells relative to noncancer retinal epithelial cells, and the improved method for the isolation of 1 is expected to facilitate further exploration of its pharmacological properties.

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Section: Resultssupporting

confidence: 58%

An Efficient Method for the Isolation of Toxins from Pteridium aquilinum and Evaluation of Ptaquiloside Against Cancer and Non-cancer Cells

et al. 2021

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“…For example, the quinomycins have been described as bis-intercalators of DNA ( Waring and Wakelin, 1974 ), which occurs at the minor groove of DNA through the insertion of two planar, heteroaromatic rings around two base pairs ( Rackham et al, 2013 ). These ligand-DNA interactions have been described in context of anti-tumour activity as selective towards rapid dividing cells, causing inhibition of DNA replication and transcription, perturbating the cell cycle and interfering with DNA repair mechanisms ( Nichol et al, 2019 ; Rahman et al, 2019 ). Further, anti-protistal activity of the quinomycins through targeting rapid dividing cells have been demonstrated in E. histolytica ( Espinosa et al, 2012 ) and Plasmodium falciparum ( Lee and Inselburg, 1993 ).…”

Section: Resultsmentioning

confidence: 99%

TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries

Lam

Vuong²,

Jex

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Trichomonas vaginalis is a neglected urogenital parasitic protist that causes 170 million cases of trichomoniasis annually, making it the most prevalent non-viral, sexually transmitted disease. Trichomoniasis treatment relies on nitroheterocyclics, such as metronidazole. However, with increasing drug-resistance, there is an urgent need for novel anti-trichomonals. Little progress has been made to translate anti-trichomonal research into commercialised therapeutics, and the absence of a standardised compound-screening platform is the immediate stumbling block for drug-discovery. Herein, we describe a simple, cost-effective growth assay for T. vaginalis and the related Tritrichomonas foetus . Tracking changes in pH were a valid indicator of trichomonad growth ( T. vaginalis and T. foetus ), allowing development of a miniaturised, chromogenic growth assay based on the phenol red indicator in 96- and 384-well microtiter plate formats. The outputs of this assay can be quantitatively and qualitatively assessed, with consistent dynamic ranges based on Z′ values of 0.741 and 0.870 across medium- and high-throughput formats, respectively. We applied this high-throughput format within the largest pure-compound microbial metabolite screen (812 compounds) for T. vaginalis and identified 43 hit compounds. We compared these identified compounds to mammalian cell lines, and highlighted extensive overlaps between anti-trichomonal and anti-tumour activity. Lastly, observing nanomolar inhibition of T. vaginalis by fumagillin, and noting this compound has reported activity in other protists, we performed in silico analyses of the interaction of fumagillin with its molecular target methionine aminopeptidase 2 for T. vaginalis , Giardia lamblia and Entamoeba histolytica , highlighting potential for fumagillin as a broad-spectrum anti-protistal against microaerophilic protists. Together, this new platform will accelerate drug-discovery efforts, underpin drug-resistance screening in trichomonads, and contributing to a growing body of evidence highlighting the potential of microbial natural products as novel anti-protistals.

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“…Nevertheless, it is fair to point out that S-MGBs with similarly tight DNA-binding selectivity have been obtained taking advantage of binding to GC base pairs and some of these have significant anticancer activity. 28,29 Studies of S-MGBs in anticancer applications have investigated in vitro activity against a number of cancers including a human colon carcinoma (HCT116), a cisplatin sensitive and cisplatin resistant ovarian cell line (A2780, A2780cis) and melanoma cancer (B16-F10) in a model of lung cancer. In the study of the first three, carried out in collaboration with scientists at the University of Huddersfield activity against the cancer cell lines was compared a human non-cancerous retinal epithelial cell line (ARPE19).…”

Section: Translating the Field: S-mgbs In Cancermentioning

confidence: 99%

“…In the study of the first three, carried out in collaboration with scientists at the University of Huddersfield activity against the cancer cell lines was compared a human non-cancerous retinal epithelial cell line (ARPE19). 29 The central points of this study were to establish that S-MGBs are effective and selective as anticancer agents, are active against cell lines resistant to standard therapy (cisplatin in this case), and do not act by an alkylation In the other study of S-MGBs from an exploratory set of 47 structurally diverse compounds, five were found to be significantly active, comparable or better to that of a standard therapy, gemcitabine. 30 [Table 2] As noted above, the target cell line was B16-f10luc.…”

Section: Translating the Field: S-mgbs In Cancermentioning

confidence: 99%

The potential for new and resilient anti-cancer drugs based upon minor groove binders for DNA

Scott

Suckling

2021

MRAJ

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Anti-infective and anticancer drugs share the serious problem that over time resistance develops to their effects leading to clinical obsolescence. Research at the University of Strathclyde has discovered a platform of anti-infective drugs based upon minor groove binders for DNA that have exceptional resilience to the development of resistance in their target organisms (bacteria, fungi, and parasites). This property is associated with the fact that the Strathclyde minor groove binders (S-MGBs) act at more than one discrete molecular target. One of the compounds has successfully completed a phase IIa clinical trial for the treatment of Clostridioides difficile infections. Several other compounds have shown activity against a number of cancer cell lines in vitro with indications of in vivo activity in a mouse model of lung cancer. This paper places these discoveries in the context of previous studies of minor groove binders as anticancer agents and considers whether the benefits of multitargeting successfully demonstrated in anti-infective applications can be translated to anticancer applications.

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Selective in vitro anti-cancer activity of non-alkylating minor groove binders

Abstract: We describe the synthesis and evaluation of Strathclyde Minor Groove Binders (S-MGBs) as selective anti-cancer agents which act through a non-alkylating mechanism.

Cited by 12 publications

References 18 publications

An Efficient Method for the Isolation of Toxins from Pteridium aquilinum and Evaluation of Ptaquiloside Against Cancer and Non-cancer Cells

An Efficient Method for the Isolation of Toxins from Pteridium aquilinum and Evaluation of Ptaquiloside Against Cancer and Non-cancer Cells

TriTOX: A novel Trichomonas vaginalis assay platform for high-throughput screening of compound libraries

The potential for new and resilient anti-cancer drugs based upon minor groove binders for DNA

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