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Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR
Cheol-Hee Choi1, Joon-Ho Kim, Sang-Hyun Kim
1Research Center for Resistant Cells, Chosun University, Gwangju 501-759, Republic of Korea. chchoi@chosun.ac.kr
Abstract:
During screening for the flavonoid chemosensitizers, it was found that 5,7,3',4',5'-pentamethoxyflavone (PMF) was equipotent to verapamil in vitro with respect to the chemosensitizing effect. PMF appears to have a chemosensitizing effect not only by increasing the intracellular accumulation of the drugs without competition in a binding site of azidopine but also by interfering with the substrate-stimulated ATPase activity. Structure-activity relationship suggests that methoxylated substitution and its numbers or sites of the rings are more important than its hydroxylated counterparts in chemosensitization. Overall, PMF is anticipated to be a novel and highly potent second-generation flavonoid chemosensitizer because PMF has significant advantages of having a high therapeutic index, of being a non-transportable inhibitor, and of having a low possibility of drug interactions at the azidopine-binding site of Pgp.
Insights
5,7,3
Area of Science:
- Pharmacology
- Medicinal Chemistry
Background:
- Chemosensitizers enhance the efficacy of chemotherapy drugs.
- Flavonoids are being investigated for their potential as chemosensitizers.
- P-glycoprotein (Pgp) is a key transporter involved in multidrug resistance.
Purpose of the Study:
- To identify novel flavonoid chemosensitizers.
- To evaluate the chemosensitizing potential of 5,7,3',4',5'-pentamethoxyflavone (PMF).
Main Methods:
- In vitro screening of flavonoid compounds for chemosensitizing effects.
- Assessing intracellular drug accumulation and P-glycoprotein (Pgp) ATPase activity.
- Structure-activity relationship analysis of methoxylated flavonoids.
Main Results:
- 5,7,3',4',5'-pentamethoxyflavone (PMF) demonstrated equipotent chemosensitizing effects compared to verapamil in vitro.
- PMF increased intracellular drug accumulation without competing at the azidopine-binding site of Pgp.
- PMF interfered with substrate-stimulated ATPase activity of Pgp.
- Methoxylated substitutions on flavonoids are crucial for chemosensitization.
Conclusions:
- PMF is a potent, second-generation flavonoid chemosensitizer.
- PMF offers advantages including a high therapeutic index, non-transportable inhibition, and low drug interaction potential at the Pgp azidopine-binding site.
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