Novel class of P-glycoprotein inhibitors from Plectranthus spp.
2020
Authors:
Isca, VeraCoelho, Jaime
Monteiro, Carlos
Ntungwe, Epole
Dominguez-Martin, Eva Maria
Dinić, Jelena
Diaz-Lanza, Ana Maria
Candeias, Nuno R.
Afonso, Carlos A.M.
Pešić, Milica
Rijo, Patricia
Document Type:
Conference object (Published version)
,
© 2020 by the COST Action CA17104
Metadata
Show full item recordAbstract:
Multidrug resistance (MDR) is one of the main challenges in cancer treatment, in which overexpression of
P-glycoprotein (P-gp) plays an important role. Therefore, there is an urgent need to identify new
compounds that can exert anticancer effects and at the same time revert MDR. In this context, Plectranthus
genus (Lamiaceae) is a great source of cytotoxic compounds that could be used as lead molecules for
drug development, such as 6,7-dehydroroyleanone (1) (P. madagascariensis (Pers.) Benth. essential oil)
and 7α-acetoxy-6β-hydroxyroyleanone (2) (P. grandidentatus Gürke) [1].
The aim of this work was to prepare a small library of new 12-O-substituted derivatives with potential P-gp
inhibitory effect by exploring the reactivity of the natural royleanones 1 and 2. In this study, we identified a
new derivative that exhibited a P-gp inhibitory activity higher than the natural diterpenes 1 and 2, and
comparable to Dexverapamil. Furthermore, this compound showed the ability to sensitize the resistant cell
line NCI-H460/R to doxorubicin. This activity was evaluated in the human non-small cell lung carcinoma
(NCI-H460) cell line and its MDR counterpart NCI-H460/R with the P-gp overexpression by using the MTT
and Rhodamine 123 accumulation assays. Further derivatizations and quantitative structure–activity
relationship analysis are ongoing to discover new derivatives with improved activity.
References: [1] Isca VMS et al. (2020). ACS Med Chem Lett. 11 (5): 839-845
Keywords:
MDR; P-gp; non-small cell lung carcinoma; PlectranthusFunding / projects:
- Support for this work was provided by FCT through UIDP/04567/2020, UIDB/04567/2020, and Ph.D. grant SFRH/BD/137671/2018. CSC-IT center for Science Ltd., Finland is acknowledged for the computational resources’ allocation. The Academy of Finland is acknowledged for the financial support to N.R.C (Decisions No. 326487 and 326486)
In:
- Abstract book: COST Action 17104 (STRATAGEM) WG3 Meeting - International Online Symposium on “New Therapeutic Tools Against Preclinical Models of Multidrug Resistant Tumors”; 2020 Nov 4; Online. COST Action CA17104; 2020. p. 30.