Evaluation of 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 as a therapeutic agent for androgen-dependent prostate cancer.
The high incidence of prostate cancer and lack of an effective, long-term treatment for metastatic disease highlights the need for more potent non-calcemic vitamin D analogs as potential alternative or combinational prostate cancer therapies. Among the analogs, 19-nor-1alpha,25-dihydroxyvitamin D2 (19-nor-1alpha,25(OH)2D2) known as paricalcitol or Zempler, has less calcemic effects and an equipotential activity as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) in several in vivo and in vitro systems. It was recently demonstrated that a modified analog of paricalcitol, 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 (MART-10) compared to 1alpha,25(OH)2D3 was more effective in inhibiting proliferation of an immortalized normal prostate cell line (PZ-HPV-7) (1,000-fold) and invasion of PC-3 prostate cancer cells (10-fold). In this study, the effects of MART-10 and 1alpha,25(OH)2D3 on proliferation, vitamin D receptor transactivation, vitamin D-binding protein (DBP) binding, CYP24A1 (24-OHase) substrate hydroxylation kinetics, and induction of CYP24A1 gene expression were compared in an androgen-dependent prostate cancer cell model, LNCaP. The results demonstrated that MART-10 was 1,000-fold more active than 1alpha,25(OH)2D3 in inhibiting LNCaP cell proliferation. MART-10 was more active than 1alpha,25(OH)2D3 in up-regulating a vitamin D receptor-responsive Luciferase construct and inducing CYP24A1 gene expression in LNCaP prostate cancer cells. In addition, MART-10 has a lower affinity for DBP and less substrate degradation by CYP24A1 compared to 1alpha,25(OH)2D3, indicating that MART-10 has more bioavailability and a longer half-life. Thus, these data suggest that MART-10 may be a potential candidate as a therapeutic agent for prostate cancer, especially for patients who fail in conventional therapies.
Flanagan
John N
JN
Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Zheng
Shasha
S
Chiang
Kun-Chun
KC
Kittaka
Atsushi
A
Sakaki
Toshiyuki
T
Nakabayashi
Sachie
S
Zhao
Xiansi
X
Spanjaard
Remco A
RA
Persons
Kelly S
KS
Mathieu
Jeffrey S
JS
Holick
Michael F
MF
Chen
Tai C
TC
D000728:Androgens / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017931:DNA Primers; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
C413745:2-hydroxypropyl-1,25-dihydroxyvitamin D3; D000728:Androgens; D017931:DNA Primers; D012333:RNA, Messenger; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase