Distinct cellular uptake patterns of two anticancer unsymmetrical bisacridines and their metabolic transformation in tumor cells.

Joanna Frąckowiak; Paweł Kubica; Michał Kosno; Agnieszka Potęga; Katarzyna Owczarek-Grzymkowska; Julia Borzyszkowska-Bukowska; Tomasz Laskowski; Ewa Paluszkiewicz; Zofia Mazerska

doi:10.1016/j.jpba.2024.116493

Distinct cellular uptake patterns of two anticancer unsymmetrical bisacridines and their metabolic transformation in tumor cells.

Abstrakt

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents. Their high cytotoxicity towards multiple human cancer cell lines and inhibition of human tumor xenograft growth in nude mice signal their potential for cancer treatment. Therefore, the mechanism of their strong biological activity is broadly investigated. Here, we explore the efflux and metabolism of UAs, as both strongly contribute to the development of drug resistance in cancer cells. We tested two highly cytotoxic UAs, C‑2028 and C‑2045, as well as their glucuronic acid and glutathione conjugates in human cancer cell lines (HepG2 and LS174T). As a point of reference for cell-based systems, we examined the rate of UA metabolic conversion in cell-free systems. A multiple reaction monitoring (MRM)-mass spectrometry (MS) method was developed in the present study for analysis of UAs and their metabolic conversion in complex biological matrices. Individual analytes were identified by several features: their retention time, mass‑to‑charge ratio and unique fragmentation pattern. The rate of UA uptake and metabolic transformation was monitored for 24 h in cell extracts and cell culture medium. Both UAs were rapidly internalized by cells. However, C‑2028 was gradually accumulated, while C‑2045 was eventually released from cells during treatment. UAs demonstrated limited metabolic conversion in cells. The glucuronic acid conjugate was excreted, whereas the glutathione conjugate was deposited in cancer cells. Our results obtained from cell-free and cell-based systems, using a uniform MRM‑MS method, will provide valuable insight into the mechanism of UA biological activity in diverse biological models.

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Autorzy (9)

Joanna Frąckowiak dr
Paweł Kubica dr inż.
Michał Kosno
Agnieszka Potęga dr hab. inż.
Katarzyna Owczarek-Grzymkowska
- Laboratorium Bioanalityczne, Gdański Uniwersytet Medyczny
Julia Borzyszkowska-Bukowska dr inż.
Tomasz Laskowski dr hab. inż.
Ewa Paluszkiewicz dr inż.
Zofia Mazerska prof. dr hab. inż.

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Kategoria:

Publikacja w czasopiśmie

Typ:

artykuły w czasopismach

Opublikowano w:

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS nr 252,
ISSN: 0731-7085

Język:

angielski

Rok wydania:

2025

Opis bibliograficzny:

Frąckowiak J., Kubica P., Kosno M., Potęga A., Owczarek-Grzymkowska K., Borzyszkowska-Bukowska J., Laskowski T., Paluszkiewicz E., Mazerska Z.: Distinct cellular uptake patterns of two anticancer unsymmetrical bisacridines and their metabolic transformation in tumor cells.// JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS -,iss. 252 (2025), s.116493-

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