Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.

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Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells

Molecules ◽

10.3390/molecules26071867 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1867

Author(s):

Nelly Durand ◽

Méliné Simsir ◽

Laurie Signetti ◽

Fabien Labbal ◽

Robert Ballotti ◽

...

Keyword(s):

Melanoma Cells ◽

Carcinoma Cells ◽

Drug Efflux ◽

Cancer Treatments ◽

Anti Cancer ◽

Efflux Inhibition ◽

Melanoma Patients ◽

Almost All ◽

Chemotherapy Efficacy ◽

Cells Death

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 BRAFV600E mutation are treated with vemurafenib, an inhibitor of BRAFV600E, 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 BRAFV600E 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.

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Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity

Biomedicines ◽

10.3390/biomedicines8080251 ◽

2020 ◽

Vol 8 (8) ◽

pp. 251

Author(s):

Anida Hasanovic ◽

Méliné Simsir ◽

Frank S. Choveau ◽

Enzo Lalli ◽

Isabelle Mus-Veteau

Keyword(s):

Adrenocortical Carcinoma ◽

Standard Treatment ◽

Treatment Effectiveness ◽

Therapeutic Option ◽

Treatment Resistance ◽

Proton Motive Force ◽

Carcinoma Cells ◽

Drug Efflux ◽

Multidrug Transporters ◽

Risk Of Relapse

Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment resistance. Here, we report the identification of a new inhibitor of Patched drug efflux, the anti-histaminergic drug astemizole. We show that astemizole enhances the cytotoxic, proapoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells at concentrations of astemizole or doxorubicin that are not effective by themselves. Our results suggest that a low concentration of astemizole sensitizes ACC cells to doxorubicin, which is a component of the standard treatment for ACC composed of etoposide, doxorubicin, cisplatin and mitotane (EDPM). Patched uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that the use of astemizole or a derivative in combination with EDPM could be a promising therapeutic option for ACC by increasing the treatment effectiveness at lower doses of EDPM, which would reduce the severe side effects of this regimen.

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MMP-9 as a Candidate Marker of Response to BRAF Inhibitors in Melanoma Patients With BRAFV600E Mutation Detected in Circulating-Free DNA

Frontiers in Pharmacology ◽

10.3389/fphar.2018.00856 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 24

Author(s):

Rossella Salemi ◽

Luca Falzone ◽

Gabriele Madonna ◽

Jerry Polesel ◽

Diana Cinà ◽

...

Keyword(s):

Brafv600e Mutation ◽

Braf Inhibitors ◽

Candidate Marker ◽

Circulating Free Dna ◽

Free Dna ◽

Melanoma Patients

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Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer

Neoplasia ◽

10.1593/neo.12640 ◽

2012 ◽

Vol 14 (7) ◽

pp. 656-IN24 ◽

Cited By ~ 30

Author(s):

Roger S. Jackson ◽

William Placzek ◽

Ana Fernandez ◽

Shabnam Ziaee ◽

Chia-Yi Chu ◽

...

Keyword(s):

Prostate Cancer ◽

Transgenic Mouse ◽

Xenograft Models ◽

Human Xenograft Models

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Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer

Oncotarget ◽

10.18632/oncotarget.1586 ◽

2013 ◽

Vol 4 (12) ◽

pp. 2451-2461 ◽

Cited By ~ 57

Author(s):

Luigi Fontana ◽

Remi M. Adelaiye ◽

Antonella L. Rastelli ◽

Kiersten Marie Miles ◽

Eric Ciamporcero ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Dietary Protein ◽

Protein Restriction ◽

Dietary Protein Restriction ◽

Xenograft Models ◽

Human Xenograft Models

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Fluconazole Resistance Associated with Drug Efflux and Increased Transcription of a Drug Transporter Gene, PDH1, inCandida glabrata

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.7.1695 ◽

1998 ◽

Vol 42 (7) ◽

pp. 1695-1701 ◽

Cited By ~ 115

Author(s):

Haruko Miyazaki ◽

Yoshitsugu Miyazaki ◽

Antonia Geber ◽

Tanya Parkinson ◽

Christopher Hitchcock ◽

...

Keyword(s):

Multidrug Transporter ◽

Drug Efflux ◽

Drug Transporter ◽

Transporter Gene ◽

Fluconazole Resistance ◽

Binding Domains ◽

Immunodeficiency Virus ◽

Susceptible Isolate ◽

High Doses

ABSTRACT Sequential Candida glabrata isolates were obtained from the mouth of a patient infected with human immunodeficiency virus type 1 who was receiving high doses of fluconazole for oropharyngeal thrush. Fluconazole-susceptible colonies were replaced by resistant colonies that exhibited both increased fluconazole efflux and increased transcripts of a gene which codes for a protein with 72.5% identity to Pdr5p, an ABC multidrug transporter in Saccharomyces cerevisiae. The deduced protein had a molecular mass of 175 kDa and was composed of two homologous halves, each with six putative transmembrane domains and highly conserved sequences of ATP-binding domains. When the earliest and most azole-susceptible isolate of C. glabrata from this patient was exposed to fluconazole, increased transcripts of thePDR5 homolog appeared, linking azole exposure to regulation of this gene.

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