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Int J Cancer. 2018 Jul 1;143(1):199-211. doi: 10.1002/ijc.31296. Epub 2018 Feb 23.

Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo.

Hasanovic A1,2,3,4, Ruggiero C1,2,3,4, Jung S5, Rapa I6, Signetti L1,2,3,4, Ben Hadj M1,2,3,4, Terzolo M6, Beuschlein F5,7, Volante M6, Hantel C5,7, Lalli E1,2,3,4, Mus-Veteau I1,2,3,4.

Author information

1
Université Côte d'Azur, Sophia Antipolis, Valbonne, France.
2
CNRS UMR7275, Sophia Antipolis, Valbonne, France.
3
NEOGENEX CNRS International Associated Laboratory, Sophia Antipolis, Valbonne, France.
4
Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Valbonne, France.
5
Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
6
Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy.
7
Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zurich, Switzerland.

Abstract

One of the crucial challenges in the clinical management of cancer is the resistance to chemotherapeutics. We recently demonstrated that the Hedgehog receptor Patched, which is overexpressed in many recurrent and metastatic cancers, is a multidrug transporter for chemotherapeutic agents such as doxorubicin. The present work provides evidences that Patched is expressed in adrenocortical carcinoma (ACC) patients, and is a major player of the doxorubicin efflux and the doxorubicin resistance in the human ACC cell line H295R. We discovered that methiothepin inhibits the doxorubicin efflux activity of Patched. This drug-like molecule enhances the cytotoxic, pro-apoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells which endogenously overexpress Patched, and thereby mitigates the resistance of these cancer cells to doxorubicin. Moreover, we report that in mice the combination of methiothepin with doxorubicin prevents the development of xenografted ACC tumors more efficiently than doxorubicin alone by enhancing the accumulation of doxorubicin specifically in tumors without obvious undesirable side effects. Our results suggest that the use of an inhibitor of Patched drug efflux such as methiothepin in combination with doxorubicin could be a promising therapeutic option for adrenocortical carcinoma, and most likely also for other Patched-expressing cancers.

KEYWORDS:

Hedgehog receptor; Patched; adrenocortical carcinoma; cancers; chemotherapy resistance; drug efflux inhibitor; drug efflux pump; multidrug resistance

PMID:
29411361
DOI:
10.1002/ijc.31296
[Indexed for MEDLINE]

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