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Mol Pharm. 2017 Nov 6;14(11):4042-4051. doi: 10.1021/acs.molpharmaceut.7b00710. Epub 2017 Oct 3.

Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin.

Author information

1
Northwestern University, Feinberg School of Medicine , Department of Urology, Chicago, Illinois 60611, United States.
2
Northwestern University , Simpson Querrey Institute for BioNanotechnology, Chicago, Illinois 60611, United States.
3
Northwestern University, Feinberg School of Medicine , Division of Hematology/Oncology, Department of Medicine, Chicago, Illinois 60611, United States.
4
Northwestern University, Feinberg School of Medicine , Department of Pathology, Chicago, Illinois 60611, United States.
5
Northwestern University, Feinberg School of Medicine , Developmental Therapeutic Institute, Chicago, Illinois 60611, United States.
6
Northwestern University, Feinberg School of Medicine , Department of Microbiology and Immunology, Chicago, Illinois 60611, United States.
7
Robert H Lurie Comprehensive Cancer Center of Northwestern University , Chicago, Illinois 60611, United States.
8
Northwestern University , International Institute for Nanotechnology (IIN), Evanston, Illinois 60208, United States.

Abstract

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.

KEYWORDS:

B-cell receptor signaling; cholesterol; high-density lipoproteins; lymphoma; nanoparticles

PMID:
28933554
PMCID:
PMC6004607
[Available on 2018-11-06]
DOI:
10.1021/acs.molpharmaceut.7b00710
[Indexed for MEDLINE]

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