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Monoterpene indole alkaloids as leads for targeting multidrug resistant cancer cells from the African medicinal plant Tabernaemontana elegans

  • Maria-José U. FerreiraEmail author
  • Angela Paterna
Article
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Abstract

Multidrug resistance (MDR) is the main challenge in cancer treatment. Several mechanisms of MDR have been proposed, such as an increased drug efflux due to the overexpression of ABC drug transporter proteins, or a deregulation of apoptosis. Thus, the development of ABC-transporter modulators and the search for effective apoptosis inducers have been considered realistic strategies for overcoming MDR. Exploiting collateral sensitivity is also comprised among the most promising approaches to tackle MDR. Aiming at obtaining a library of monoterpene indole alkaloids for overcoming MDR, we have been carrying out the phytochemical study of the African medicinal plant Tabernaemontana elegans (Apocynaceae), by using both approaches isolation and molecular derivatization. The results, summarized in this review, showed that several indole alkaloids, of both natural origin or obtained by derivatization, are promising potential lead structures for reversing MDR.

Keywords

ABC-transporters Apocynaceae Apoptosis Collateral sensitivity BCRP, MRP1, and P-gp 

Abbreviations

ABC

ATP Binding Cassette

ABCB1

ATP Binding Cassette, Subfamily B, Member 1

ABCC1

ATP Binding Cassette, Subfamily C, Member 1

ABCG2

ATP Binding Cassette, Subfamily G, Member 2

ADMET

Absorption, distribution, metabolism, excretion, toxicity

ADP-ribose

Adenosine diphosphate ribose

ATP

Adenosine triphosphate

BBB

Blood–brain barrier

Bcl-2

B-cell lymphoma 2

BCRP

Breast cancer resistance protein

BHK-21-wt

Baby hamster kidney-21 wild-type cells

CS

Collateral sensitivity

FAR

Fluorescence activity ratio

GSH

Glutathione

GSSG

Glutathione disulphide

HCT116

Human colon carcinoma cell line

HEK293

Human embryonic kidney 293 cells

HepG2

Human liver carcinoma cell line

HuH-7

Human liver carcinoma cell line

IC50

Sample concentration causing 50% inhibition

log P

Octanol/water partition coefficient

MDR

Multidrug resistance

MRP1

Multidrug resistance associated protein 1

MTS

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NIH-3T3

Mouse embryonic fibroblast cells

PAR

Parental cells

P-gp

P-glycoprotein

ROS

Reactive oxygen species

RR

Relative resistance ratio

SAR

Structure-activity relationship

SW620

Human Caucasian colon adenocarcinoma

XIAP

X-linked inhibitor of apoptosis protein

Notes

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Faculty of Pharmacy, Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL)University of LisbonLisbonPortugal

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