Pinocytosis as the Biological Mechanism That Protects Pgp Function in Multidrug Resistant Cancer Cells and in Blood–Brain Barrier Endothelial Cells

Omran, Ziad; Whitehouse, Chloe; Halwani, Majed; Zamzami, Mazin A.; Baothman, Othman A.; Rauch, Cyril

Abstract

Cancer is the second leading cause of death worldwide. Chemotherapy has shown reasonable success in treating cancer. However, multidrug resistance (MDR), a phenomenon by which cancerous cells become resistant to a broad range of functionally and structurally unrelated chemotherapeutic agents, is a major drawback in the effective use of chemotherapeutic agents in the clinic. Overexpression of P-glycoprotein (Pgp) is a major cause of MDR in cancer as it actively effluxes a wide range of structurally and chemically unrelated substrates, including chemotherapeutic agents. Interestingly, Pgp is also overexpressed in the endothelial cells of blood–brain barrier (BBB) restricting the entry of 98% small molecule drugs to the brain. The efficacy of Pgp is sensitive to any impairment of the membrane structure. A small increase of 2% in the membrane surface tension, which can be caused by a very low drug concentration, is enough to block the Pgp function. We demonstrate in this work by mathematical equations that the incorporation of drugs does increase the surface tension as expected, and the mechanism of endocytosis dissipates any increase in surface tension by augmenting the internalisation of membrane per unit of time, such that an increase in the surface tension of about 2% can be dissipated within only 4.5 s.

Citation

Omran, Z., Whitehouse, C., Halwani, M., Zamzami, M. A., Baothman, O. A., & Rauch, C. (2020). Pinocytosis as the Biological Mechanism That Protects Pgp Function in Multidrug Resistant Cancer Cells and in Blood–Brain Barrier Endothelial Cells. Symmetry, 12(8), Article 1221. https://doi.org/10.3390/sym12081221

• Journal Article Type: Article
• Acceptance Date: Jul 23, 2020
• Online Publication Date: Jul 25, 2020
• Publication Date: 2020-08
• Deposit Date: Aug 24, 2020
• Publicly Available Date: Aug 24, 2020
• Journal: Symmetry
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 8
• Article Number: 1221
• DOI: https://doi.org/10.3390/sym12081221
• Keywords: Computer Science (miscellaneous); Physics and Astronomy (miscellaneous); Chemistry (miscellaneous); General Mathematics
• Public URL: https://nottingham-repository.worktribe.com/output/4849572
• Publisher URL: https://www.mdpi.com/2073-8994/12/8/1221