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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Cathepsin L inhibition suppresses drug resistance in vitro and in vivo: a putative mechanism

Xin Zheng,^1,* Fei Chu,^1,* Pauline M. Chou,¹ Christine Gallati,³ Usawadee Dier,³ Bernard L. Mirkin,^1,2, Shaker A. Mousa,³ and Abdelhadi Rebbaa³

¹Department of Pediatrics, Children's Memorial Research Center, Children's Memorial Hospital, Chicago; ²Molecular Pharmacology and Biological Chemistry, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and ³Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York

Submitted 14 February 2008 ; accepted in final form 21 October 2008

Cathepsin L is a lysosomal enzyme thought to play a key role in malignant transformation. Recent work from our laboratory has demonstrated that this enzyme may also regulate cancer cell resistance to chemotherapy. The present study was undertaken to define the relevance of targeting cathepsin L in the suppression of drug resistance in vitro and in vivo and also to understand the mechanism(s) of its action. In vitro experiments indicated that cancer cell adaptation to increased amounts of doxorubicin over time was prevented in the presence of a cathepsin L inhibitor, suggesting that inhibition of this enzyme not only reverses but also prevents the development of drug resistance. The combination of the cathepsin L inhibitor with doxorubicin also strongly suppressed the proliferation of drug-resistant tumors in nude mice. An investigation of the underlying mechanism(s) led to the finding that the active form of this enzyme shuttles between the cytoplasm and nucleus. As a result, its inhibition stabilizes and enhances the availability of cytoplasmic and nuclear protein drug targets including estrogen receptor-, Bcr-Abl, topoisomerase-II, histone deacetylase 1, and the androgen receptor. In support of this, the cellular response to doxorubicin, tamoxifen, imatinib, trichostatin A, and flutamide increased in the presence of the cathepsin L inhibitor. Together, these findings provided evidence for the potential role of cathepsin L as a target to suppress cancer resistance to chemotherapy and uncovered a novel mechanism by which protease inhibition-mediated drug target stabilization may enhance cellular visibility and, thus, susceptibility to anticancer agents.

drug resistance; topoisomerase; histone deacetylase 1; estrogen receptor