title: Activation of the Constitutive Androstane Receptor Increases the Therapeutic Index of CHOP in Lymphoma Treatment.
abstract: The constitutive androstane receptor (CAR and NR1i3) is a key regulator of CYP2B6, the enzyme predominantly responsible for the biotransformation of cyclophosphamide (CPA) to its pharmacologically active metabolite, 4-hydroxycyclophosphamide (4-OH-CPA). Previous studies from our laboratory illustrated that CAR activation increases the formation of 4-OH-CPA; however, CPA is rarely used clinically outside of combination therapies. Here, we hypothesize that including a selective human CAR activator with the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen can improve the efficacy without exacerbating off-target toxicity of this regimen in non-Hodgkin lymphoma treatment. In this study, we have developed a novel multiorgan coculture system containing human primary hepatocytes for hepatic metabolism, lymphoma cells as a model target for CHOP, and cardiomyocytes as a major site of off-target toxicity associated with this regimen. We found that a selective human CAR activator, CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime), altered expression of key drug-metabolizing enzymes and transporters in human hepatocytes, which positively affects the metabolic profile of CHOP. Coadministration of CITCO and CHOP in the coculture model led to significantly enhanced cytotoxicity in lymphoma cells but not in cardiomyocytes. Moreover, the beneficial effects of CITCO were abrogated when CAR knockout HepaRG cells were used in the coculture model. Importantly, synergistic anticancer effects were observed between CITCO and CHOP, in that inclusion of CITCO alongside the CHOP regimen offers comparable antineoplastic activity toward lymphoma cells at significantly reduced drug concentrations, and the decreased CHOP load attenuates cardiotoxicity. Overall, these findings provide a potentially promising novel strategy for facilitating CHOP-based chemotherapy.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland.
authors.forename: William D
authors.initials: WD
authors.lastname: Hedrich
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Bioreclamation IVT, Baltimore, Maryland.
authors.forename: Scott
authors.initials: S
authors.lastname: Heyward
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Junran
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Maryland School of Medicine and Stewart Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland.
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Hassan
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland. hwang@rx.umaryland.edu.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D000090702:Constitutive Androstane Receptor; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation; D011241:Prednisone / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000090702:Constitutive Androstane Receptor; D006657:Histones; C000716327:NR1I3 protein, human; C000716329:Nr1i3 protein, rat; D010091:Oximes; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C475093:6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime; D011241:Prednisone
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