Human bone marrow niche chemoprotection mediated by cytochrome p450 enzymes

// Salvador Alonso 1 , Meng Su 1 , Jace W. Jones 2 , Sudipto Ganguly 1 , Maureen A. Kane 2 , Richard J. Jones 1 , Gabriel Ghiaur 1 1 Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, MD, USA 2 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA Correspondence to: Gabriel Ghiaur, e-mail: gghiaur1@jhmi.edu Keywords: drug resistance, leukemia, microenvironment, CYP, multiple myeloma Received: January 31, 2015      Accepted: March 14, 2015      Published: April 10, 2015 ABSTRACT Substantial evidence now demonstrates that interactions between the tumor microenvironment and malignant cells are a critical component of clinical drug resistance. However, the mechanisms responsible for microenvironment-mediated chemoprotection remain unclear. We showed that bone marrow (BM) stromal cytochrome P450 (CYP)26 enzymes protect normal hematopoietic stem cells (HSCs) from the pro-differentiation effects of retinoic acid. Here, we investigated if stromal expression of CYPs is a general mechanism of chemoprotection. We found that similar to human hepatocytes, human BM-derived stromal cells expressed a variety of drug-metabolizing enzymes. CYP3A4, the liver’s major drug-metabolizing enzyme, was at least partially responsible for BM stroma’s ability to protect multiple myeloma (MM) and leukemia cells from bortezomib and etoposide, respectively, both in vitro and in vivo . Moreover, clarithromycin overcame stromal-mediated MM resistance to dexamethasone, suggesting that CYP3A4 inhibition plays a role in its ability to augment the activity of lenalidomide and dexamethasone as part of the BiRd regimen. We uncovered a novel mechanism of microenvironment-mediated drug resistance, whereby the BM niche creates a sanctuary site from drugs. Targeting these sanctuaries holds promise for eliminating minimal residual tumor and improving cancer outcomes.