TY - JOUR
T1 - Differentiation-inducing potency of the seco-steroid JK-1624F2-2 can be increased by combination with an antioxidant and a p38MAPK inhibitor which upregulates the JNK pathway
AU - Zhang, Jing
AU - Posner, Gary H.
AU - Danilenko, Michael
AU - Studzinski, George P.
N1 - Funding Information:
We thank Dr. Milan Uskokovic, Bioxell, Nutley, NJ, for the generous gift of 1,25-dihydroxyvitamin D 3 , as well as Ms. Ayelet Shabtay and Ms. Orly Freiv (Ben-Gurion University, Beer-Sheva, Israel) for excellent assistance in the experiments on murine leukemia cells. This work was supported by NIH grants R01-CA-44722 (to GPS), CA-93547 (to GHP), and AICR grant 05A022 to GPS and MD.
PY - 2007/6/1
Y1 - 2007/6/1
N2 - Low calcemic analogs of vitamin D are candidates for differentiation therapy of human myeloid leukemias. We report here that the seco-steroid synthesized to have resistance to intracellular degradation and low calcemia-inducing activity, 1alpha-hydroxymethyl-3beta-16-ene-24,24-difluoro-25-hydroxy-vitamin D3 (JKF), induces monocytic differentiation in four established human myeloid leukemia cell lines, HL60, U937, THP-1, NB-4, and murine myeloid leukemia cells WEHI-3B D-. JKF has differentiation-inducing potency which is slightly lower than the physiologically active form of vitamin D, 1,25(OH)2vitamin D3 (1,25D). However, simultaneous addition of carnosic acid (CA), an antioxidant, and SB20190 (SB), an inhibitor of p38MAP kinase, increases the differentiation efficiency of JKF to a level similar to the level observed when 1,25D is used in such combinations. We also show for the first time that SB inhibits the phosphorylation of MAPKAPK2, a downstream target of p38MAPK, but upregulates the phosphorylation of at least one of the isoforms of JNK (p46 JNK1) and of c-jun in all four human myeloid cell lines studied here. These studies indicate that the JNK1 pathway is positively associated with monocytic differentiation of several subtypes of myeloid leukemia cells arrested at different developmental stages. Further, since JKF is less calcemic than 1,25D, the data suggest that JKF combined with CA and SB is likely to have a therapeutic advantage over 1,25D-based experimental regimens for myeloid leukemias.
AB - Low calcemic analogs of vitamin D are candidates for differentiation therapy of human myeloid leukemias. We report here that the seco-steroid synthesized to have resistance to intracellular degradation and low calcemia-inducing activity, 1alpha-hydroxymethyl-3beta-16-ene-24,24-difluoro-25-hydroxy-vitamin D3 (JKF), induces monocytic differentiation in four established human myeloid leukemia cell lines, HL60, U937, THP-1, NB-4, and murine myeloid leukemia cells WEHI-3B D-. JKF has differentiation-inducing potency which is slightly lower than the physiologically active form of vitamin D, 1,25(OH)2vitamin D3 (1,25D). However, simultaneous addition of carnosic acid (CA), an antioxidant, and SB20190 (SB), an inhibitor of p38MAP kinase, increases the differentiation efficiency of JKF to a level similar to the level observed when 1,25D is used in such combinations. We also show for the first time that SB inhibits the phosphorylation of MAPKAPK2, a downstream target of p38MAPK, but upregulates the phosphorylation of at least one of the isoforms of JNK (p46 JNK1) and of c-jun in all four human myeloid cell lines studied here. These studies indicate that the JNK1 pathway is positively associated with monocytic differentiation of several subtypes of myeloid leukemia cells arrested at different developmental stages. Further, since JKF is less calcemic than 1,25D, the data suggest that JKF combined with CA and SB is likely to have a therapeutic advantage over 1,25D-based experimental regimens for myeloid leukemias.
KW - ATF-2
KW - Differentiation
KW - JNK
KW - MAPK
KW - Myeloid leukemias
KW - Vitamin D
KW - c-jun
KW - p38
UR - http://www.scopus.com/inward/record.url?scp=34547657573&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2007.01.003
DO - 10.1016/j.jsbmb.2007.01.003
M3 - Article
AN - SCOPUS:34547657573
SN - 0960-0760
VL - 105
SP - 140
EP - 149
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 1-5
ER -