The Effects of Selected Sesquiterpenes from Myrica rubra Essential Oil on the Efficacy of Doxorubicin in Sensitive and Resistant Cancer Cell Lines.

Martin Ambrož,Kateřina Žáková,Lenka Skálová,Adam Skarka,Petra Matoušková,Martina Zajdlová

doi:10.3390/molecules22061021

Martin Ambrož, Kateřina Žáková + Show 4 more

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https://doi.org/10.3390/molecules22061021

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Abstract

β-caryophyllene oxide (CAO), α-humulene (HUM), trans-nerolidol (NER) and valencene (VAL) are constituents of the essential oil of Myrica rubra (MEO), which has significant antiproliferative effect in various cancer cell lines. In the present study, we compared the antiproliferative effect of these sesquiterpenes alone and in combination with the cytostatic drug doxorubicin (DOX) in cancer cell lines with different sensitivity to DOX. Two ovarian cancer cell lines (sensitive A2780 and partly resistant SKOV3) and two lymphoblast cancer cell lines (sensitive CCRF/CEM and completely resistant CEM/ADR) were used. The observed effects varied among sesquiterpenes and also differed in individual cell lines, with only VAL being effective in all the cell lines. A strong synergism of DOX with NER was found in the A2780 cells, while DOX acted synergistically with HUM and CAO in the SKOV3 cells. In the CCRF/CEM cells, a synergism of DOX with CAO and NER was observed. In resistant CEM/ADR cells, sesquiterpenes did not increase DOX efficacy, although they significantly increased accumulation of DOX (up to 10-times) and rhodamine-123 (substrate of efflux transporter ABCB1) within cancer cells. In conclusion, the tested sesquiterpenes were able to improve DOX efficacy in the sensitive and partly resistant cancer cells, but not in cells completely resistant to DOX.

Highlights

Sesquiterpenes, defined as 15-carbon compounds formed from 3 isoprenoid units, represent an extremely diverse, heterogeneous and large group of natural compounds
These compounds might be detected among sesquiterpenes, as these substances are able to enhance drug uptake via increased membrane permeability
We showed the ability of Myrica rubra essential oil and its sesquiterpene components

Summary

Introduction

Sesquiterpenes, defined as 15-carbon compounds formed from 3 isoprenoid units, represent an extremely diverse, heterogeneous and large group of natural compounds. Sesquiterpenes are secondary metabolites, formed mainly in plants, fungi, bacteria and marine invertebrates [1,2,3]. Sesquiterpenes represent the major components of plant essential oils, widely used in folk medicines, health-supporting preparations and cosmetics. Many sesquiterpenes possess a broad spectrum of interesting biological activities including anti-cancer ones [4]. They have shown promising effects in various cancer cell lines, where they interfered with the cell cycle and apoptosis as well as increased the production of reactive oxygen species (ROS) and affected cell migration and adhesion [5,6,7]. A combination of the α-methylene sesquiterpene lacton eremophila-1(10)11(13)-dien-12, 8β-olide with cisplatin or paclitaxel increased the effect of these cytostatics in the Molecules 2017, 22, 1021; doi:10.3390/molecules22061021 www.mdpi.com/journal/molecules

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