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Novel Inhibitors of P-Glycoprotein O...

Follit, Courtney A.

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Novel Inhibitors of P-Glycoprotein Overcome Multidrug Resistance in Human Cancer Cell Lines.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Novel Inhibitors of P-Glycoprotein Overcome Multidrug Resistance in Human Cancer Cell Lines./
作者:	Follit, Courtney A.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
面頁冊數:	182 p.
附註:	Source: Dissertation Abstracts International, Volume: 78-11(E), Section: B.
Contained By:	Dissertation Abstracts International78-11B(E).
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10283145
ISBN:	9781369867183

Novel Inhibitors of P-Glycoprotein Overcome Multidrug Resistance in Human Cancer Cell Lines.
Follit, Courtney A.

Novel Inhibitors of P-Glycoprotein Overcome Multidrug Resistance in Human Cancer Cell Lines. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 182 p.

Source: Dissertation Abstracts International, Volume: 78-11(E), Section: B.

Thesis (Ph.D.)--Southern Methodist University, 2017.

Multidrug resistance (MDR) due to the overexpression of ATP dependent efflux transporters such as P-glycoprotein (P-gp) is a major obstacle to the successful pharmacological treatment of cancer. P-gp is able to export the majority of commonly used chemotherapeutic drugs from the cell, thereby conferring resistance. Inhibitors of P-gp have tremendous potential as co-therapeutic agents as they could be used to restore sensitivity of MDR cancers to traditional chemotherapeutics and to prevent cancers from developing a MDR phenotype. Unfortunately, no such P-gp inhibitors are currently available.

ISBN: 9781369867183Subjects--Topical Terms:

3172791
Cellular biology.

Novel Inhibitors of P-Glycoprotein Overcome Multidrug Resistance in Human Cancer Cell Lines.
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520 $a Multidrug resistance (MDR) due to the overexpression of ATP dependent efflux transporters such as P-glycoprotein (P-gp) is a major obstacle to the successful pharmacological treatment of cancer. P-gp is able to export the majority of commonly used chemotherapeutic drugs from the cell, thereby conferring resistance. Inhibitors of P-gp have tremendous potential as co-therapeutic agents as they could be used to restore sensitivity of MDR cancers to traditional chemotherapeutics and to prevent cancers from developing a MDR phenotype. Unfortunately, no such P-gp inhibitors are currently available.
520 $a The majority of previously identified P-gp inhibitors have themselves been substrates of the protein and have all failed in clinical trials. For this reason, inhibitors that interact specifically with the nucleotide binding domain and are not transport substrates may be better drug-lead candidates. In silico drug docking was used to screen millions of drug-like molecules to identify lead compounds predicted to interact with the nucleotide binding domain of P-gp with higher affinity than the drug binding domain [Wise, Biochemistry 51: 5125-5141, 2012; Brewer et al., Mol Pharm 86: 716-726, 2014; McCormick et al., 2017 in preparation]. 88 compounds identified by these methods were tested for their ability to restore chemosensitivity in a P-gp overexpressing prostate cancer cell line model of MDR to elucidate their suitability as novel P-gp inhibitor drug-leads. 29 compounds were observed to sensitize the MDR cell line to paclitaxel at non-toxic concentrations and 25 compounds were shown to display synergism with paclitaxel. The calcein-AM live cell assay was used to test P-gp inhibition for 19 of the synergistic compounds. Inhibition of P-gp mediated efflux was observed for 18 compounds, which suggests that the restoration of paclitaxel sensitivity observed in the cancer cell line may be the result of P-gp inhibition. Additionally, 12 of the 18 inhibitory compounds were previously reported to have no significant stimulatory effects on basal ATPase activity of P-gp in detergent micelles (Brewer et al., Mol Pharm 86: 716-726), indicating they did not interact with the protein in the manner typical of transport substrates.
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