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

Xin Zheng, Fei Chu, Pauline M. Chou, Christine Gallati, Usawadee Dier, Bernard L. Mirkin, Shaker A. Mousa, Abdelhadi Rebbaa

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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-α, Bcr-Abl, topoisomerase-IIα, 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.

Original languageEnglish (US)
Pages (from-to)C65-C74
JournalAmerican Journal of Physiology - Cell Physiology
Volume296
Issue number1
DOIs
StatePublished - Jan 1 2009

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Zheng, X., Chu, F., Chou, P. M., Gallati, C., Dier, U., Mirkin, B. L., Mousa, S. A., & Rebbaa, A. (2009). Cathepsin L inhibition suppresses drug resistance in vitro and in vivo: A putative mechanism. American Journal of Physiology - Cell Physiology, 296(1), C65-C74. https://doi.org/10.1152/ajpcell.00082.2008