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Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells.

Authors :
Durand N
Simsir M
Signetti L
Labbal F
Ballotti R
Mus-Veteau I
Source :
Molecules (Basel, Switzerland) [Molecules] 2021 Mar 26; Vol. 26 (7). Date of Electronic Publication: 2021 Mar 26.
Publication Year :
2021

Abstract

We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells. Here, we show that methiothepin also inhibits doxorubicin efflux and increases doxorubicin cytotoxicity in melanoma cells which endogenously overexpress Ptch1. Melanoma patients having the BRAF <superscript>V600E</superscript> mutation are treated with vemurafenib, an inhibitor of BRAF <superscript>V600E</superscript> , often in combination with trametinib, an inhibitor of MEK. Almost all patients ultimately acquire resistance to the treatment leading to disease progression. Here, we report that methiothepin overcomes the resistance of BRAF <superscript>V600E</superscript> melanoma cells by enhancing the cytotoxicity of vemurafenib and trametinib on these cells leading to melanoma cells death. We observe that the addition of methiothepin to vemurafenib prevents migration of resistant melanoma cells more efficiently than vemurafenib alone. Our results provide an additional proof that Ptch1 drug efflux inhibition increases the effectiveness of anti-cancer treatments and overcomes resistance of melanoma cells expressing Ptch1.

Details

Language :
English
ISSN :
1420-3049
Volume :
26
Issue :
7
Database :
MEDLINE
Journal :
Molecules (Basel, Switzerland)
Publication Type :
Academic Journal
Accession number :
33810240
Full Text :
https://doi.org/10.3390/molecules26071867