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Cells 2018, 7(8), 107; https://doi.org/10.3390/cells7080107

Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency

1
Université Côte d’Azur, Campus Valrose, 06100 Nice, France
2
CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France
3
NEOGENEX CNRS International Associated Laboratory, Sophia Antipolis, 06560 Valbonne, France
*
Author to whom correspondence should be addressed.
Received: 1 July 2018 / Revised: 8 August 2018 / Accepted: 11 August 2018 / Published: 14 August 2018
(This article belongs to the Special Issue Targeting Hedgehog Signaling in Cancer)
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Abstract

One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. Recent studies showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries have identified several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. In vivo proof of concept has been performed in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers. View Full-Text
Keywords: Hedgehog receptor Ptch1; efflux pump; multidrug resistance; transporter; cancer therapy Hedgehog receptor Ptch1; efflux pump; multidrug resistance; transporter; cancer therapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Hasanovic, A.; Mus-Veteau, I. Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency. Cells 2018, 7, 107.

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