Human bone marrow niche chemoprotection mediated by cytochrome p450 enzymes

Salvador Alonso, Meng Su, Jace W. Jones, Sudipto Ganguly, Maureen A. Kane, Richard J Jones, Gabriel Ghiaur

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)14905-14912
Number of pages8
JournalOncotarget
Volume6
Issue number17
StatePublished - 2015

Fingerprint

Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP3A
Bone Marrow
Multiple Myeloma
Drug Resistance
Dexamethasone
Pharmaceutical Preparations
Tumor Microenvironment
Clarithromycin
Residual Neoplasm
Etoposide
Enzymes
Hematopoietic Stem Cells
Tretinoin
Mesenchymal Stromal Cells
Birds
Cell Differentiation
Hepatocytes
Leukemia
Liver

Keywords

  • CYP
  • Drug resistance
  • Leukemia
  • Microenvironment
  • Multiple myeloma

ASJC Scopus subject areas

  • Oncology

Cite this

Human bone marrow niche chemoprotection mediated by cytochrome p450 enzymes. / Alonso, Salvador; Su, Meng; Jones, Jace W.; Ganguly, Sudipto; Kane, Maureen A.; Jones, Richard J; Ghiaur, Gabriel.

In: Oncotarget, Vol. 6, No. 17, 2015, p. 14905-14912.

Research output: Contribution to journalArticle

Alonso, S, Su, M, Jones, JW, Ganguly, S, Kane, MA, Jones, RJ & Ghiaur, G 2015, 'Human bone marrow niche chemoprotection mediated by cytochrome p450 enzymes', Oncotarget, vol. 6, no. 17, pp. 14905-14912.
Alonso, Salvador ; Su, Meng ; Jones, Jace W. ; Ganguly, Sudipto ; Kane, Maureen A. ; Jones, Richard J ; Ghiaur, Gabriel. / Human bone marrow niche chemoprotection mediated by cytochrome p450 enzymes. In: Oncotarget. 2015 ; Vol. 6, No. 17. pp. 14905-14912.
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