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

• Published in: PloS one 2017-01, Vol.12 (1), p.e0168938
• Main Authors: El-Araby, Moustafa E, Omar, Abdelsattar M, Khayat, Maan T, Assiri, Hanan A, Al-Abd, Ahmed M
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Antineoplastic Agents, Phytogenic - pharmacology; ATP; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors; ATPases; Biology and Life Sciences; Cancer therapies; Care and treatment; Cell Line, Tumor; Chemical synthesis; Chemotherapy; Clinical trials; Colorectal cancer; Colorectal carcinoma; Curcumin - chemistry; Curcumin - pharmacology; Cytotoxicity; Dosage and administration; Doxorubicin; Drug Design; Drug resistance; Drug Resistance, Multiple - drug effects; Drug Screening Assays, Antitumor; Drug Synergism; Efflux; Entrapment; Enzymes; Glycoproteins; Humans; Kinases; Medicine and Health Sciences; Microbial drug resistance; Molecular Mimicry; Multidrug resistance; Multidrug resistant organisms; Organic chemistry; Oxazolone; P-Glycoprotein; Paclitaxel; Paclitaxel - pharmacology; Pharmaceuticals; Pharmacology; Pharmacy; Physical Sciences; Proteins; Research and Analysis Methods; Studies; Substrates; Suppressors; Synergistic effect; Toxicity; Tumor cell lines; Tumor cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0168938

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.