Imidazoacridinone antitumor agent C-1311 as a selective mechanism-based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes

Potęga, Agnieszka; Fedejko-Kap, Barbara; Mazerska, Zofia

doi:10.1016/j.pharep.2016.02.003

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…The inhibition of topoisomerase II by C-1311 leads to the formation of cleavable DNA-topoisomerase II complexes and subsequent DNA strand breaks [ 2 ]. However, more recent studies have described additional roles for C-1311; the inhibition of tumor angiogenesis through the targeting of the HIF-1α/VEGF pathway [ 3 ], inactivation of the human cytochrome P450 1A2 and 3A4 isoenzymes [ 4 ], and inhibition of receptor kinases, most notably the FMS-like tyrosine kinase FLT3 [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

et al. 2017

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C-1311 is a small molecule, which has shown promise in a number of pre-clinical and clinical studies. However, the biological response to C-1311 exposure is complicated and has been reported to involve a number of cell fates. Here, we investigated the molecular signaling which determines the response to C-1311 in both cancer and non-cancer cell lines. For the first time we demonstrate that the tumor suppressor, p53 plays a key role in cell fate determination after C-1311 treatment. In the presence of wild-type p53, cells exposed to C-1311 entered senescence. In contrast, cells lines without functional p53 underwent mitotic catastrophe and apoptosis. C-1311 also induced autophagy in a non-p53-dependent manner. Cells in hypoxic conditions also responded to C-1311 in a p53-dependent manner, suggesting that our observations are physiologically relevant. Most importantly, we show that C-1311 can be effectively combined with radiation to improve the radiosensitivity of a panel of cancer cell lines. Together, our data suggest that C-1311 warrants further clinical testing in combination with radiotherapy for the treatment of solid tumors.

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Section: Introductionmentioning

confidence: 99%

The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

et al. 2017

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“…Moreover, the metabolic profiles of C-1305 and C-1311 were not changed in MCF-7 and HCT116 cells after their overexpression with P4503A4 isoenzyme [47]. Thus, P4503A4 does not take part in the metabolism of studied acridinone derivatives, as we previously showed with recombinant isoenzymes in a non-cellular system [26,27] and in HepG2 cells [29,31]. EV.…”

Section: Metabolic Transformation Of C-1305 and C-1311 In Mcf-7 And Hmentioning

confidence: 59%

“…During long-term treatment of HCT116-CYP3A4 cells with C-1305 and C-1311, the activity of P4503A4 also gradually increased up to 96 h of incubation, then started to go down after 120 h. Concluding, we show that C-1305 and C-1311 are strong P4503A4 inducers. However, our previous studies in non-cellular systems revealed that C-1305 and C-1311 incubated with recombinant P4503A4 as its selective mechanism-based inactivator [25,26] but later in HepG2 cells showed that in living cells C-1305 increased activity of P4503A4 [50]. It suggests that the activation of P4503A4 catalytic properties does not result from direct interaction between the compounds and the P450 enzyme but through a cellular regulatory pathway and this activation is stronger than any direct drug inhibition features.…”

Section: Modulation Of P4503a4 and Ugt1a10 Activity By C-1305 And C-1311mentioning

confidence: 95%

“…It was shown previously that although cytochromes P450 are not involved in C-1305 and C-1311 activation in non-cellular systems; both compounds were shown to be selective irreversible inhibitors of P4501A2 and P4503A4. This inhibition was shown to be mechanism-based for both compounds [25,26]. Each compound was also found to be metabolized with human recombinant flavin-containing monooxygenases 1 and 3 (FMO1, FMO3) [27,28].…”

Section: Introductionmentioning

confidence: 91%

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Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response

Pawłowska

Kwaśniewska

Mazerska

et al. 2020

IJMS

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Activity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studies in non-cellular systems showed that they are mechanism-based inhibitors of cytochrome P4503A4 and undergo glucuronidation via UDP-glucuronosyltranspherase 1A10 isoenzyme (UGT1A10). Therefore, we investigated the potency of these compounds to modulate P4503A4 and UGT1A10 activity in breast MCF-7 and colon HCT116 cancer cells and their influence on cytotoxicity and cellular response in cells with different expression levels of studied isoenzymes. We show that C-1305 and C-1311 are inducers of not only P4503A4 but also UGT1A10 activity. MCF-7 and HCT116 cells with high P4503A4 activity are more sensitive to acridinone derivatives and undergo apoptosis/necrosis to a greater extent. UGT1A10 was demonstrated to be responsible for C-1305 and C-1311 glucuronidation in cancer cells and glucuronide products were excreted outside the cell very fast. Finally, we show that glucuronidation of C-1305 antitumor agent enhances its pro-apoptotic properties in HCT116 cells, while the cytotoxicity and cellular response induced by C-1311 did not change after drug glucuronidation in both cell lines.

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Cytochrome P450 Inhibition

2020

Human Drug Metabolism

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Imidazoacridinone antitumor agent C-1311 as a selective mechanism-based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes

Cited by 6 publications

References 31 publications

The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response

Cytochrome P450 Inhibition

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