Low-calcemic, efficacious, 1α,25-dihydroxyvitamin D3 analog QW-1624F2-2: calcemic dose–response determination, preclinical genotoxicity testing, and revision of A-ring stereochemistry

Posner, Gary H.; Jeon, Heung Bae; Sarjeant, Amy Narducci; Riccio, Edward S.; Doppalapudi, Rupa S.; Kapetanović, Izet M.; Saha, Uttam Kumar; Dolan, Patrick; Kensler, Thomas W.

doi:10.1016/j.steroids.2004.09.004

Cited by 30 publications

(27 citation statements)

References 16 publications

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“…The transient induction of CYP24 observed with QW may relate to the fact that CYP24 is an inducible enzyme in nonrenal tissues (55). A recent report using V79 hamster cells stably overexpressing human CYP24 (56) showed that QW is at least 10 times more potent in blocking CYP24 activity than the commonly used P450 inhibitor ketoconazole.…”

Section: Discussionmentioning

confidence: 99%

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

Sundaram¹,

Beckman

Bajwa

et al. 2006

Molecular Cancer Therapeutics

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The enzyme 24-hydroxylase, also known as CYP24, metabolizes 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and is an established marker of vitamin D activity. Our studies evaluated the influence of a low-calcemic 1,25(OH) 2 D 3 analogue, QW-1624F2-2 (QW), on the regulation of CYP24 expression in MKL-4 cells, a metastatic mammary tumor cell model. 1,25(OH) 2 D 3 and its analogue, EB 1089, stimulated CYP24 induction at both protein and transcript levels. In contrast, QW failed to produce a sustained stimulation of CYP24, due, in large part, to a reduction in the stability of the CYP24 message. QW enhanced the capacity of 1,25(OH) 2 D 3 and EB 1089 to inhibit tumor cell proliferation by f2-fold. QW also blocked the sustained induction of CYP24 expression by 1,25(OH) 2 D 3 and EB 1089, increased the potency of 1,25(OH) 2 D 3 and EB 1089, and inhibited breast tumor cell proliferation and invasion.

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Section: Discussionmentioning

confidence: 99%

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

Sundaram¹,

Beckman

Bajwa

et al. 2006

Molecular Cancer Therapeutics

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“…The most commonly used example is the antibiotic ketoconazole (54), but the nonspecific nature of this compound means that it is also a potent inhibitor of 1a-hydroxylase activity. To alleviate this potentially detrimental effect, compounds that selectively inhibit 24-hydroxylase have been developed (55,56) together with 24-hydroxylase-resistant vitamin D analogues (57). Studies to date suggest that this may be fruitful avenue in the quest to potentiate the anticancer effects of 1,25(OH) 2 D 3 (58).…”

Section: Vitamin D Metabolism In Breast Cancermentioning

confidence: 99%

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

Townsend

Banwell

Guy

et al. 2005

Clinical Cancer Research

165

138

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Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer. Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D^activating enzyme 1a-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1a-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.Results: Expression of mRNA for 1a-hydroxylase (27-fold; P < 5 Â 10 À11), vitamin D receptor (7-fold; P < 1.5 Â 10 À8 ), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1a-Hydroxylase enzyme activity was also higher in tumors (44.3 F 11.4 versus12.4 F 4.8 fmol/h/mg protein in nonneoplastic tissue; P < 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D 3 was also significantly higher in tumors (84.8 F 11.7 versus 33.6 F 8.5fmol/h/mg protein; P < 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH) 2 D 3 . Conclusion: These data indicate that the vitamin D^activating enzyme 1a-hydroxylase is upregulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH) 2 D 3 production in tumors by catalyzing catabolism to less active vitamin D metabolites.The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer.

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“…The cells were passaged and fed with medium 2-3 times per week to maintain the log phase growth. 1,25D was a kind gift from Dr. Milan Uskokovic, BioXell, Inc., Nutley, NJ., and its analog JKF was synthesized as previously described [17,26]. Carnosic acid (CA) was purchased from Alexis Corporation (San Diego, CA.)…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

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

Zhang¹,

Posner²,

Danilenko³

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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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 D 3 (JKF), induces monocytic differentiation in four established human myeloid leukemia cell lines, HL60, U937, THP-1, NB4, 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) 2 vitamin D 3 (1,25D). However, simultaneous addition of carnosic acid (CA), an antioxidant, and SB20190 (SB), an inhibitor of p38 MAP 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 MAPKAPK-2, 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.

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Low-calcemic, efficacious, 1α,25-dihydroxyvitamin D3 analog QW-1624F2-2: calcemic dose–response determination, preclinical genotoxicity testing, and revision of A-ring stereochemistry

Cited by 30 publications

References 16 publications

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

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

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