Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer

Tadi, Kiranmayi; Ashok, Badithe T.; Chen, Yuangen; Banerjee, Debabrata; Wysocka-Skrzela, B.; Konopa, Jerzy; Darżynkiewicz, Zbigniew; Tiwari, Raj K.

doi:10.4161/cbt.7.3.6029

Cited by 4 publications

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“…1-Nitro-9-aminoacridine derivative Capridine β, 9[2′-hydroxyethylamino]-4-methyl-1-nitroacridine (also known as C-1748) ( Figure 1 ), similar to m-AMSA, exhibited anti-cancer and antifungal properties [ 14 , 15 , 16 ]. Moreover, previous studies, performed for Capridine β in cancer cell cultures and human xenograft animal models indicated a high therapeutic index and low cytotoxicity with the potential for clinical development [ 14 , 15 , 17 , 18 , 19 ]. Both compounds, m-AMSA, as well as Capridine β, contain an acridine chromophore ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Due to the fact that m-AMSA, a 9-aminoacridine derivative, is a human topoisomerase II poison and has been shown to have a moderate inhibitory effect on fungal topoisomerase II [ 11 ] along with a high therapeutic index, low cytotoxicity of Capridine β [ 14 , 15 , 17 , 18 , 19 ], antifungal activity [ 16 ], and acridine chromophore similarity to m-AMSA, we have decided to deeply analyze its antifungal potential as well as mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

et al. 2021

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In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine β (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine β antifungal activity depends on the kind of strains analyzed (MICs range 0.5–64 μg mL−1) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine β reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine β, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine β only slightly diminished the catalytic activity of yTOPOII.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

et al. 2021

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“…C-1748-9-[(2 0 -Hydroxyethylamino)-4-methyl-1-nitroacridine] belongs to a group of 9-amino-1-nitroacridine antitumor agents (Konopa et al, 1981) shown to be efficacious against cancer in cell culture (HCT8 and HT29 colon cancer cells) (Augustin et al, 2010) and in nude mice xenografts created using colon (HCT8) and prostate (LnCaP, JCA, PC3, TSU) cancer cell lines (Chen et al, 2002;Tadi et al, 2005Tadi et al, , 2007. C-1748 has low mutagenic potential and only slight myelosuppressive properties (Narayanan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

CYP3A4‐dependent cellular response does not relate to CYP3A4‐catalysed metabolites of C‐1748 and C‐1305 acridine antitumor agents in HepG2 cells

Augustin

Niemira

Hołownia

et al. 2014

Cell Biology International

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High CYP3A4 expression sensitizes tumor cells to certain antitumor agents while for others it can lower their therapeutic efficacy. We have elucidated the influence of CYP3A4 overexpression on the cellular response induced by antitumor acridine derivatives, C-1305 and C-1748, in two hepatocellular carcinoma (HepG2) cell lines, Hep3A4 stably transfected with CYP3A4 isoenzyme, and HepC34 expressing empty vector. The compounds were selected considering their different chemical structures and different metabolic pathways seen earlier in human and rat liver microsomes C-1748 was transformed to several metabolites at a higher rate in Hep3A4 than in HepC34 cells. In contrast, C-1305 metabolism in Hep3A4 cells was unchanged compared to HepC34 cells, with each cell line producing a single metabolite of comparable concentration. C-1748 resulted in a progressive appearance of sub-G1 population to its high level in both cell lines. In turn, the sub-G1 fraction was dominated in CYP3A4-overexpressing cells following C-1305 exposure. Both compounds induced necrosis and to a lesser extent apoptosis, which were more pronounced in Hep3A4 than in wild-type cells. In conclusion, CYP3A4-overexpressing cells produce higher levels of C-1748 metabolites, but they do not affect the cellular responses to the drug. Conversely, cellular response was modulated following C-1305 treatment in CYP3A4-overexpressing cells, although metabolism of this drug was unaltered.

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Amino acid or peptide conjugates of acridine/acridone and quinoline/quinolone-containing drugs. A critical examination of their clinical effectiveness within a twenty-year timeframe in antitumor chemotherapy and treatment of infectious diseases

Kukowska

2017

European Journal of Pharmaceutical Sciences

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Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer

Abstract: During the editorial office formatting of Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer

Cited by 4 publications

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Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

Antifungal Activity of Capridine β as a Consequence of Its Biotransformation into Metabolite Affecting Yeast Topoisomerase II Activity

CYP3A4‐dependent cellular response does not relate to CYP3A4‐catalysed metabolites of C‐1748 and C‐1305 acridine antitumor agents in HepG2 cells

Amino acid or peptide conjugates of acridine/acridone and quinoline/quinolone-containing drugs. A critical examination of their clinical effectiveness within a twenty-year timeframe in antitumor chemotherapy and treatment of infectious diseases

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