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Novel Gemini vitamin D 3 analogs: Large structure/function analysis and ability to induce antimicrobial peptide
Author(s) -
Okamoto Ryoko,
Gery Sigal,
Kuwayama Yoshio,
Borregaard Niels,
Ho Quoc,
Alvarez Rocio,
Akagi Tadayuki,
Liu George Y.,
Uskokovic Milan R.,
Koeffler H. Phillip
Publication year - 2013
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.28328
Subject(s) - potency , vitamin d and neurology , cathelicidin , antimicrobial , myeloid leukemia , peptide , leukemia , pharmacology , antimicrobial peptides , biology , in vitro , chemistry , immunology , endocrinology , biochemistry , microbiology and biotechnology
We have synthesized 39 1,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] analogs having two side chains attached to carbon‐20 (Gemini) with various modifications and compared their anticancer activities. Five structure–function rules emerged to identify analogs with enhanced anticancer activity. One of these active analogs, BXL‐01‐0126, was more potent than 1,25(OH) 2 D 3 in mediating 50% clonal inhibition of cancer cell growth. Murine studies found that BXL‐01‐0126 and 1,25(OH) 2 D 3 had nearly the same potency to raise serum calcium levels. Taken together, BXL‐01‐0126 when compared to 1,25(OH) 2 D 3 has greater anticancer potency, but similar toxicity causing hypercalcemia. We focused on the effect of these compounds on the stimulation of expression of human cathelicidin antimicrobial peptide ( CAMP ) whose gene has a vitamin D response element in its promoter. Expression of CAMP mRNA and protein increased in a dose‐response fashion after exposure of acute myeloid leukemia (AML) cells to the Gemini analog, BXL‐01‐126, in vitro . A xenograft model of AML was developed using U937 AML cells injected into NSG‐immunodeficient mice. Administration of vitamin D 3 compounds to these mice resulted in substantial levels of CAMP in the systemic circulation. This suggests a unique prophylactic treatment at diagnosis or during induction chemotherapy for AML patients to provide them with protection against various microbial infections through CAMP induction.