In silico comparisons between natural inhibitors of ABCB1/P-glycoprotein to overcome doxorubicin-resistance in the NCI/ADR-RES cell line

Mohamed A. Morsy, Azza A.K. El-Sheikh, Ahmed R.N. Ibrahim, Mohammed A. Khedr, Abdulla Y. Al-Taher

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX)-resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose-dependently, PIP significantly increased intracellular accumulation of rhodamine-123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50 μM significantly potentiated DOX-induced cytotoxicity on the same cell line. P-gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC50 of 84 ± 1 and 37 ± 2 μM, respectively. PIP did not show any activation of ATPase activity, while DOX did, indicating that P-gp does not accept PIP as a substrate. Using DOX at concentration 33.33 μM together with PIP (100 μM), DOX-mediated P-gp ATPase activity was decreased to levels 4-folds lower than DOX alone. In conclusion, both in silico and in vitro studies confirm that PIP is an inhibitor of P-gp mediated DOX efflux, suggesting PIP as a promising adjuvant to DOX cancer chemotherapy.

Original languageEnglish
Pages (from-to)87-94
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume112
DOIs
Publication statusPublished - 15 Jan 2018

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piperine
P-Glycoprotein
Computer Simulation
Doxorubicin
Cell Line
Adenosine Triphosphatases
Rhodamine 123
Molecular Dynamics Simulation

Keywords

  • ATPase activity
  • Doxorubicin
  • Molecular docking
  • P-glycoprotein
  • Piperine

Cite this

@article{19bba9dc2aa84009ba6a8bcb7a53a795,
title = "In silico comparisons between natural inhibitors of ABCB1/P-glycoprotein to overcome doxorubicin-resistance in the NCI/ADR-RES cell line",
abstract = "To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX)-resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose-dependently, PIP significantly increased intracellular accumulation of rhodamine-123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50 μM significantly potentiated DOX-induced cytotoxicity on the same cell line. P-gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC50 of 84 ± 1 and 37 ± 2 μM, respectively. PIP did not show any activation of ATPase activity, while DOX did, indicating that P-gp does not accept PIP as a substrate. Using DOX at concentration 33.33 μM together with PIP (100 μM), DOX-mediated P-gp ATPase activity was decreased to levels 4-folds lower than DOX alone. In conclusion, both in silico and in vitro studies confirm that PIP is an inhibitor of P-gp mediated DOX efflux, suggesting PIP as a promising adjuvant to DOX cancer chemotherapy.",
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author = "Morsy, {Mohamed A.} and El-Sheikh, {Azza A.K.} and Ibrahim, {Ahmed R.N.} and Khedr, {Mohammed A.} and Al-Taher, {Abdulla Y.}",
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language = "English",
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In silico comparisons between natural inhibitors of ABCB1/P-glycoprotein to overcome doxorubicin-resistance in the NCI/ADR-RES cell line. / Morsy, Mohamed A.; El-Sheikh, Azza A.K.; Ibrahim, Ahmed R.N.; Khedr, Mohammed A.; Al-Taher, Abdulla Y.

In: European Journal of Pharmaceutical Sciences, Vol. 112, 15.01.2018, p. 87-94.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - In silico comparisons between natural inhibitors of ABCB1/P-glycoprotein to overcome doxorubicin-resistance in the NCI/ADR-RES cell line

AU - Morsy, Mohamed A.

AU - El-Sheikh, Azza A.K.

AU - Ibrahim, Ahmed R.N.

AU - Khedr, Mohammed A.

AU - Al-Taher, Abdulla Y.

PY - 2018/1/15

Y1 - 2018/1/15

N2 - To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX)-resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose-dependently, PIP significantly increased intracellular accumulation of rhodamine-123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50 μM significantly potentiated DOX-induced cytotoxicity on the same cell line. P-gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC50 of 84 ± 1 and 37 ± 2 μM, respectively. PIP did not show any activation of ATPase activity, while DOX did, indicating that P-gp does not accept PIP as a substrate. Using DOX at concentration 33.33 μM together with PIP (100 μM), DOX-mediated P-gp ATPase activity was decreased to levels 4-folds lower than DOX alone. In conclusion, both in silico and in vitro studies confirm that PIP is an inhibitor of P-gp mediated DOX efflux, suggesting PIP as a promising adjuvant to DOX cancer chemotherapy.

AB - To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX)-resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose-dependently, PIP significantly increased intracellular accumulation of rhodamine-123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50 μM significantly potentiated DOX-induced cytotoxicity on the same cell line. P-gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC50 of 84 ± 1 and 37 ± 2 μM, respectively. PIP did not show any activation of ATPase activity, while DOX did, indicating that P-gp does not accept PIP as a substrate. Using DOX at concentration 33.33 μM together with PIP (100 μM), DOX-mediated P-gp ATPase activity was decreased to levels 4-folds lower than DOX alone. In conclusion, both in silico and in vitro studies confirm that PIP is an inhibitor of P-gp mediated DOX efflux, suggesting PIP as a promising adjuvant to DOX cancer chemotherapy.

KW - ATPase activity

KW - Doxorubicin

KW - Molecular docking

KW - P-glycoprotein

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DO - 10.1016/j.ejps.2017.11.010

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JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

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