Journal
PHARMACEUTICALS
Volume 15, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ph15030356
Keywords
P-glycoprotein; multidrug resistance; acute myeloid leukemia cell; P-gp inhibitors; phytol; heptacosane
Categories
Funding
- [PJ_AUTF_160829_D15]
- [FFR-D15-005355]
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Drug resistance in cancer therapy is a major problem, involving multiple factors. This study found that the compounds phytol and heptacosane from Euphorbia intisy essential oil can improve P-gp-mediated drug transport and reverse drug resistance in tumor cells.
Drug resistance is the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, and remains a major problem in cancer therapy. Resistance mechanisms are multifactorial and involve more strictly pharmacological factors, such as P-glycoprotein (P-gp) and biological factors such as inhibitor of apoptosis proteins (IAPs) and the nuclear factor-kappa B (NF-kappa B) pathway. Possible therapeutic strategies for the treatment of acute myeloid leukemia (AML) have increased in recent years; however, drug resistance remains a problem for most pa-tients. Phytol and heptacosane are the major compounds of Euphorbia intisy essential oil (EO) which were demonstrated to inhibit P-gp in a multidrug resistant in vitro model of AML. This study investigated the mechanism by which phytol and heptacosane improve P-gp-mediated drug transport. Phytol suppresses the P-gp expression via NF-kappa B inhibition and does not seem to act on the efflux system. Heptacosane acts as a substrate and potent P-gp inhibitor, demonstrating the ability to retain the substrate doxorubicin inside the cell and enhancing its cytotoxic effects. Our results suggest that these compounds act as non-toxic modulators of P-gp through different mechanisms and are able to revert P-gp-mediated drug resistance in tumor cells.
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