Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel

Moustafa E El-Araby; Abdelsattar M Omar; Maan T Khayat; Hanan A Assiri; Ahmed M Al-Abd

doi:10.1371/journal.pone.0168938

Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel

PLoS One. 2017 Jan 9;12(1):e0168938. doi: 10.1371/journal.pone.0168938. eCollection 2017.

Authors

Moustafa E El-Araby^{1

2}, Abdelsattar M Omar^{1

3}, Maan T Khayat¹, Hanan A Assiri⁴, Ahmed M Al-Abd^{5

6}

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁴ Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Department of Pharmacology, Medical Division, National Research Centre, Cairo, Egypt.

Abstract

P-glycoprotein (Pgp) is a membrane bound efflux pump spread in a variety of tumor cells and considered as a main component of multidrug resistance (MDR) to chemotherapies. In this work, three groups of compounds (imidazolone, oxazolone and vinyl dipeptide derivatives) were synthesized aiming to develop a molecular framework that effectively suppresses MDR. When tested for their influence on Pgp activity, four compounds coded Cur1-01, Cur1-12V, Curox-1 and Curox-3 significantly decreased remaining ATP concentration indicating Pgp substrate site blocking. On the other hand, Cur-3 and Cur-10 significantly increased remaining ATP concentration, which is indicative of Pgp ATPase inhibition. The cytotoxicity of synthesized compounds was examined against Pgp expressing/highly resistant colorectal cancer cell lines (LS-174T). Compounds Cur-1 and Cur-3 showed considerable cytotoxicity with IC50 values of 7.6 and 8.9 μM, respectively. Equitoxic combination (at IC50 concentrations) of PTX and Cur-3 greatly diminished resistant cell clone from 45.7% to 2.5%, albeit with some drop in potency from IC50 of 7.9 nM to IC50 of 23.8 nM. On the other hand, combination of PTX and the non-cytotoxic Cur1-12V (10 μM) significantly decreased the IC50 of PTX to 3.8 nM as well as the resistant fraction to 16.2%. The combination test was confirmed using the same protocol but on another resistant CRC cell line (HCT-116) as we obtained similar results. Both Cur-3 and Cur1-12V (10 μM) significantly increased the cellular entrapment of Pgp probe (doxorubicin) elevating its intracellular concentration from 1.9 pmole/cell to 3.0 and 2.9 pmole/cell, respectively.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
Antineoplastic Agents, Phytogenic / pharmacology*
Cell Line, Tumor
Curcumin / chemistry
Curcumin / pharmacology
Drug Design
Drug Resistance, Multiple / drug effects*
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Molecular Mimicry*
Paclitaxel / pharmacology*

Substances

ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents, Phytogenic
Curcumin
Paclitaxel

Grants and funding

This Project was funded by the Deanship of Scientific Research (DSR), at King Abdulaziz University, Jeddah, Saudi Arabia, under grant no. G-416-166-36. The authors, therefore, acknowledge with thanks DSR for technical and financial support, http://dsr.kau.edu.sa/Default.aspx?Site_ID=305&Lng=EN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.