CITCO as an Adjuvant Facilitates CHOP-Based Lymphoma Treatment in hCAR-Transgenic Mice.

Abstract

Non-Hodgkin's lymphoma (NHL) is a malignant cancer originating in the lymphatic system with a 25-30% mortality rate. CHOP, consisting of cyclophosphamide (CPA), doxorubicin, vincristine, and prednisone, is a first-generation chemotherapy extensively used to treat NHL. However, poor survival rates among patients in advanced stages of NHL shows a need to improve this standard of care treatment. CPA, an integral component of CHOP, is a prodrug that requires CYP2B6-mediated bioactivation to 4-hydroxy-CPA (4-OH-CPA). The expression of CYP2B6 is transcriptionally regulated by the constitutive androstane receptor (CAR, NRi13). We have previously demonstrated that the induction of hepatic CYP2B6 by CITCO, a selective human CAR (hCAR) agonist, results in CHOP's enhanced antineoplastic effects in vitro. Here, we investigate the in vivo potential of CITCO as an adjuvant of CPA-based NHL treatment in a hCAR-transgenic mouse line. Our results demonstrate that the addition of CITCO to the CHOP regimen leads to significant suppression of the growth of EL-4 xenografts in hCAR-transgenic mice accompanied by reduced expression of cyclin-D1, ki67, Pcna, and increased caspase 3 fragmentation in tumor tissues. CITCO robustly induced the expression of cyp2b10 (murine ortholog of CYP2B6) through hCAR activation and increased plasma concentrations of 4-OH-CPA. Comparing to intraperitoneal injection, oral gavage of CITCO results in optimal hepatic cyp2b10 induction. Our in vivo studies have collectively uncovered CITCO as an effective facilitator for CPA-based NHL treatment with a pharmacokinetic profile favoring oral administration, promoting CITCO as a promising adjuvant candidate for CPA-based regimens.

• Authors: Ritika Kurian, William Hedrich, Bryan Mackowiak, Linhao Li, Hongbing Wang
• Journal: Cells (Cells) Vol. 9 Issue 11 (11 21 2020) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 33233444 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Vincristine
• Doxorubicin
• Cyclophosphamide
• Prednisone

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Chemotherapy, Adjuvant (methods)
• Chromatography, Liquid (methods)
• Cyclophosphamide (pharmacology, therapeutic use)
• Doxorubicin (pharmacology, therapeutic use)
• Humans
• Lymphoma (drug therapy)
• Mass Spectrometry (methods)
• Mice
• Mice, Transgenic
• Prednisone (pharmacology, therapeutic use)
• Vincristine (pharmacology, therapeutic use)