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CYP24, the enzyme that catabolizes the antiproliferative agent vitamin D, is increased in lung cancer
Author(s) -
Parise Robert A.,
Egorin Merrill J.,
Kanterewicz Beatriz,
Taimi Mohammed,
Petkovich Martin,
Lew April M.,
Chuang Samuel S.,
Nichols Mark,
ElHefnawy Talal,
Hershberger Pamela A.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22058
Subject(s) - lung cancer , cancer research , downregulation and upregulation , cell culture , enzyme , lung , cancer , medicine , biology , biochemistry , genetics , gene
1α,25‐Dihydroxyvitamin D 3 (1,25D 3 ) displays potent antiproliferative activity in a variety of tumor model systems and is currently under investigation in clinical trials in cancer. Studies were initiated to explore its potential in nonsmall cell lung cancer (NSCLC), as effective approaches to the treatment of that disease are needed. In evaluating factors that may affect activity in NSCLC, the authors found that CYP24 (25‐hydroxyvitamin D 3 ‐24‐hydroxylase), the enzyme that catabolizes 1,25D 3 , is frequently expressed in NSCLC cell lines but not in the nontumorigenic bronchial epithelial cell line, Beas2B. CYP24 expression by RT‐PCR was also detected in 10/18 primary lung tumors but in only 1/11 normal lung tissue specimens. Tumor‐specific CYP24 upregulation was confirmed at the protein level via immunoblot analysis of patient‐matched normal lung tissue and lung tumor extracts. Enzymatically active CYP24 is expected to desensitize NSCLC cells to 1,25D 3 . The authors therefore implemented a high performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS) assay for 1,25D 3 and its CYP24‐generated metabolites to determine whether NSCLC cells express active enzyme. Analysis of NSCLC cell cultures revealed time‐dependent loss of 1,25D 3 coincident with the appearance of CYP24‐generated metabolites. MK‐24( S )‐S(O)(NH)‐Ph‐1, a specific inhibitor of CYP24, slowed the loss of 1,25D 3 and increased 1,25D 3 half‐life. Furthermore, combination of 1,25D 3 with MK‐24( S )‐S(O)(NH)‐Ph‐1 resulted in a significant decrease in the concentration of 1,25D 3 required to achieve maximum growth inhibition in NSCLC cells. These data suggest that increased CYP24 expression in lung tumors restricts 1,25D 3 activity and support the preclinical evaluation of CYP24 inhibitors for lung cancer treatment. © 2006 Wiley‐Liss, Inc.