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Front. Pharmacol. | doi: 10.3389/fphar.2018.00136

Molecular determinants of sensitivity or resistance of cancer cells towards sanguinarine

 Mohamed Saeed1, Nuha Mahmoud1, Yoshikazu Sugimoto2,  Thomas Efferth1* and  Heba Abdel-Aziz1*
  • 1Johannes Gutenberg-Universität Mainz, Germany
  • 2Faculty of Pharmacy, Keio University, Tokyo, Japan, Germany

For decades, natural products represent a significant source of diverse and unique bioactive lead compounds in drug discovery field. In Clinical oncology, complete tumors remission is hampered by the development of drug-resistance. Therefore, development of cytotoxic agents that may overcome drug resistance is urgently needed. Here, the natural benzophenanthridine alkaloid sanguinarine has been studied for its cytotoxic activity against multidrug resistance (MDR) cancer cells. We investigated the role of the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5 in drug resistance. Further drug resistance mechanisms analyzed in this study were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). Multidrug resistant cells overexpressing BCRP, ABCB5 and mutated ∆EGFR were not cross-resistant towards sanguinarine. Interestingly, P-gp overexpressing cells were hypersensitive to sanguinarine. Doxorubicin uptake assay carried by flow cytometry revealed that sanguinarine is a potent inhibitor of the P-gp transporter. Moreover, immunoblotting analysis proved that P-gp was downregulated in a dose dependent manner after treating P-gp overexpressing cells with sanguinarine. It was surmised that The inhibition of NFκB activity might explain the collateral sensitivity in CEM/ADR5000 cells. The COMPARE and hierarchical cluster analyses of transcriptome-wide expression profiles of tumor cell lines of the National Cancer Institute identified genes involved in various cellular processes (immune response, inflammation signaling, cell migration and microtubule formation) significantly correlated with log10IC50 values for sanguinarine. In conclusion, sanguinarine may have therapeutic potential for treating multidrug resistant tumors.

Keywords: bioinformatics, Cancer, Drug Resistance, Microarray, pharmacogenomics, Phytotherapy

Received: 23 Nov 2017; Accepted: 07 Feb 2018.

Edited by:

Vincent Kam Wai Wong, Macau University of Science and Technology, Macau

Reviewed by:

Wei Zhang, Macau University of Science and Technology, China
William Chi-Shing Tai, Hong Kong Polytechnic University, Hong Kong  

Copyright: © 2018 Saeed, Mahmoud, Sugimoto, Efferth and Abdel-Aziz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Thomas Efferth, Johannes Gutenberg-Universität Mainz, Mainz, Germany,
Dr. Heba Abdel-Aziz, Johannes Gutenberg-Universität Mainz, Mainz, Germany,