Tyrosine kinase inhibitors vandetanib, lenvatinib and cabozantinib modulate oxidation of an anticancer agent ellipticine catalyzed by cytochromes P450 in vitro

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F18%3A10386222" target="_blank" >RIV/00216208:11130/18:10386222 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/62156489:43210/18:43915452 RIV/00216208:11310/18:10386222 RIV/00064203:_____/18:10386222

Výsledek na webu

<a href="http://www.nel.edu/tyrosine-kinase-inhibitors-vandetanib-lenvatinib-and-cabozantinib-modulate-oxidation-of-an-anticancer-agent-ellipticine-catalyzed-by-cytochromes-p450-in-vitro-2642/" target="_blank" >http://www.nel.edu/tyrosine-kinase-inhibitors-vandetanib-lenvatinib-and-cabozantinib-modulate-oxidation-of-an-anticancer-agent-ellipticine-catalyzed-by-cytochromes-p450-in-vitro-2642/</a>

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

Tyrosine kinase inhibitors vandetanib, lenvatinib and cabozantinib modulate oxidation of an anticancer agent ellipticine catalyzed by cytochromes P450 in vitro

Popis výsledku v původním jazyce

OBJECTIVES: Vandetanib, lenvatinib, and cabozantinib are tyrosine kinase inhibitors (TKIs) targeting VEGFR subtypes 1 and 2, EGFR and the RET-tyrosine kinase, thus considered as multiple TKIs. These TKIs have already been approved for treating patients suffering from thyroid cancer and renal cell carcinoma. Ellipticine, a DNA-damaging drug, is another anticancer agent that is effective against certain tumors of the thyroid gland, ovarian carcinoma, breast cancer and osteolytic breast cancer metastasis. Its anticancer efficiency is dictated by its oxi-dation with cytochrome P450 (CYP) and peroxidase enzymes. A number of stud-ies testing the effectiveness of individual anticancer drugs, the pharmacological efficiencies of which are affected by their metabolism, alone or in a combination with other cytostatics demonstrated that such combination can have both positive and negative effects on treatment regimen. The aim of this study was to study the effect of vandetanib, lenvatinib and cabozantinib on oxidation of ellipticine which dictates its pharmacological efficiency. METHODS: Ellipticine oxidation catalyzed by hepatic microsomes, recombinant CYP enzymes and peroxidases (horseradish peroxidase, lactoperoxidase and myeloperoxidase) and the effect of TKIs (vandetanib, lenvatinib and cabozan-tinib) on this oxidation were analyzed by HPLC used for separation of ellipticine metabolites and quantification of their amounts formed during oxidation. RESULTS: The CYP enzymatic system oxidizes ellipti-cine up to five metabolites (9-hydroxy-, 12-hydroxy-, 13-hydroxy-, 7-hydroxyellipticine, and ellipticine N2- oxide), while peroxidases form predominantly ellipticine dimer. Ellipticine oxidation catalyzed by rat and human hepatic microsomes was inhibited by van-detanib and cabozantinib, but essentially no inhibition was caused by lenvatinib. Of individual CYP enzymes catalyzing oxidation of ellipticine, TKIs inhibited oxidation of ellipticine catalyzed by CYP2D6 &gt; 2D1 &gt; 2C9 &gt; 3A1 &gt; 3A4, the CYP enzymes participating in ellipticine oxidation to metabolites increasing the ellip-ticine anticancer efficiency. On the contrary, they have essentially no inhibition effect on ellipticine oxidation catalyzed by CYP1A1 and 1A2, which are the enzymes that predominantly detoxify this drug. All tested TKIs had essentially no effect on oxidation of ellipticine by used peroxidases. CONCLUSION: The results found demonstrate that TKIs vandetanib, lenvatinib and cabozantinib cause a decrease in oxidative activation of DNA-damaging drug ellipticine by several CYP enzymes in vitro which might lead to a decrease in its pharmacological efficiency. In contrast, they practically do not influence its detoxifica-tion catalyzed by CYP1A1, 1A2 and peroxidases. The present study indicates that tested TKIs seem not to have a potency to increase ellipticine anticancer effi-ciency.

Název v anglickém jazyce

Tyrosine kinase inhibitors vandetanib, lenvatinib and cabozantinib modulate oxidation of an anticancer agent ellipticine catalyzed by cytochromes P450 in vitro

Popis výsledku anglicky

OBJECTIVES: Vandetanib, lenvatinib, and cabozantinib are tyrosine kinase inhibitors (TKIs) targeting VEGFR subtypes 1 and 2, EGFR and the RET-tyrosine kinase, thus considered as multiple TKIs. These TKIs have already been approved for treating patients suffering from thyroid cancer and renal cell carcinoma. Ellipticine, a DNA-damaging drug, is another anticancer agent that is effective against certain tumors of the thyroid gland, ovarian carcinoma, breast cancer and osteolytic breast cancer metastasis. Its anticancer efficiency is dictated by its oxi-dation with cytochrome P450 (CYP) and peroxidase enzymes. A number of stud-ies testing the effectiveness of individual anticancer drugs, the pharmacological efficiencies of which are affected by their metabolism, alone or in a combination with other cytostatics demonstrated that such combination can have both positive and negative effects on treatment regimen. The aim of this study was to study the effect of vandetanib, lenvatinib and cabozantinib on oxidation of ellipticine which dictates its pharmacological efficiency. METHODS: Ellipticine oxidation catalyzed by hepatic microsomes, recombinant CYP enzymes and peroxidases (horseradish peroxidase, lactoperoxidase and myeloperoxidase) and the effect of TKIs (vandetanib, lenvatinib and cabozan-tinib) on this oxidation were analyzed by HPLC used for separation of ellipticine metabolites and quantification of their amounts formed during oxidation. RESULTS: The CYP enzymatic system oxidizes ellipti-cine up to five metabolites (9-hydroxy-, 12-hydroxy-, 13-hydroxy-, 7-hydroxyellipticine, and ellipticine N2- oxide), while peroxidases form predominantly ellipticine dimer. Ellipticine oxidation catalyzed by rat and human hepatic microsomes was inhibited by van-detanib and cabozantinib, but essentially no inhibition was caused by lenvatinib. Of individual CYP enzymes catalyzing oxidation of ellipticine, TKIs inhibited oxidation of ellipticine catalyzed by CYP2D6 &gt; 2D1 &gt; 2C9 &gt; 3A1 &gt; 3A4, the CYP enzymes participating in ellipticine oxidation to metabolites increasing the ellip-ticine anticancer efficiency. On the contrary, they have essentially no inhibition effect on ellipticine oxidation catalyzed by CYP1A1 and 1A2, which are the enzymes that predominantly detoxify this drug. All tested TKIs had essentially no effect on oxidation of ellipticine by used peroxidases. CONCLUSION: The results found demonstrate that TKIs vandetanib, lenvatinib and cabozantinib cause a decrease in oxidative activation of DNA-damaging drug ellipticine by several CYP enzymes in vitro which might lead to a decrease in its pharmacological efficiency. In contrast, they practically do not influence its detoxifica-tion catalyzed by CYP1A1, 1A2 and peroxidases. The present study indicates that tested TKIs seem not to have a potency to increase ellipticine anticancer effi-ciency.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA18-10251S" target="_blank" >GA18-10251S: Komplexní pohled na mechanismus působení a metabolismus inhibitorů tyrosinkinas a studium přístupů k potenciaci jejich protinádorové účinnosti</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Neuroendocrinology Letters

ISSN

0172-780X

e-ISSN

—

Svazek periodika

39

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

SE - Švédské království

Počet stran výsledku

10

Strana od-do

515-524

Kód UT WoS článku

000462136800005

EID výsledku v databázi Scopus

—