Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo. Issue 1 (23rd February 2018)

• Record Type: Journal Article
• Authors: Hasanovic, Anida; Ruggiero, Carmen; Jung, Sara; Rapa, Ida; Signetti, Laurie; Ben Hadj, Monia; Terzolo, Massimo; Beuschlein, Felix; Volante, Marco; Hantel, Constanze; Lalli, Enzo; Mus‐Veteau, Isabelle
• Is Part Of: International journal of cancer. Volume 143:Issue 1(2018)
• Page Start: 199
• Page End: 211
• Publication Date: 2018-02-23
• Subjects: chemotherapy resistance -- Patched -- Hedgehog receptor -- multidrug resistance -- drug efflux pump -- drug efflux inhibitor -- cancers -- adrenocortical carcinoma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31296
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? Multidrug resistance to chemotherapy can develop when membrane proteins pump drugs out of cancer cells faster than the drugs can kill them. In this study, the authors found that a compound called methiothepin inhibits drug efflux that is mediated by a protein called Patched. They then found that adding methiothepin to doxorubicin is more effective in blocking tumor growth in vivo than doxorubicin alone. These results suggest that methiothepin may be a valuable adjunct to chemotherapy in cancers that overexpress Patched.