Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative.
Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative.
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DOI：
10.1007/s13346-017-0379-2
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发表时间：
2017-08
影响因子：
5.4
通讯作者：
Davies NM
中科院分区：
文献类型：
--
作者：
Alrushaid S;Zhao Y;Sayre CL;Maayah ZH;Forrest ML;Senadheera SN;Chaboyer K;Anderson HD;El-Kadi AOS;Davies NM
Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC. Antioxidant activity, CYP3A4 inhibition, and P-gp inhibitory effects were examined using commercial assay kits. Drug potency was assessed utilizing triple-negative murine breast cancer cells, and cardiotoxicity was assessed utilizing adult rat and human cardiomyocytes (RL-14). Levels of reactive oxygen species and gene expression of cardiotoxicity markers, oxidative stress markers, and CYP1B1 were determined in RL-14. DoxQ was less cytotoxic to both rat and human cardiomyocytes and retained anticancer activity. Levels of ROS and markers of oxidative stress demonstrate lower oxidative damage induced by DoxQ compared to doxorubicin. DoxQ also inhibited the expression and catalytic activity of CYP1B1. Additionally, DoxQ inhibited CYP3A4 and demonstrated higher cellular uptake by MDCK-MDR cells than doxorubicin. DoxQ provides a novel therapeutic approach to mitigate the cardiotoxicity and poor oral bioavailability of doxorubicin. The cardioprotective mechanism of DoxQ likely involves scavenging ROS and CYP1B1 inhibition, while the mechanism of improving the poor oral bioavailability of doxorubicin is likely related to inhibiting CYP3A4 and P-gp.
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DOI：
10.1016/j.ijbiomac.2014.02.028
发表时间：
2014-05-01
影响因子：
8.2
作者：
Agudelo, Daniel;Bourassa, Philippe;Tajmir-Riahi, Heidar-Ali
通讯作者：
Tajmir-Riahi, Heidar-Ali
影响因子：
3.7
作者：
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Yano N
DOI：
10.1016/j.bbadis.2007.05.002
发表时间：
2007-09-01
影响因子：
6.2
作者：
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通讯作者：
Kvasnickova, Eva
DOI：
10.1016/j.jconrel.2010.04.006
发表时间：
2010-09-01
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
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作者：
Cai S;Thati S;Bagby TR;Diab HM;Davies NM;Cohen MS;Forrest ML
通讯作者：
Forrest ML
影响因子：
11
作者：
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通讯作者：
Chou HC