Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis

Kensler, Thomas W.; Dolan, Patrick; Gange, Stephen J.; Lee, Jae Kyoo; Wang, Qiang; Posner, Gary H.

doi:10.1093/carcin/21.5.341

Cited by 36 publications

(41 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, 1,25(OH) 2 D 3 is said to protect keratinocytes against UVB-induced direct DNAdamage [own unpublished results and Wong et al, 2004]. In vivo studies on mouse skin carcinogenesis are inconclusive: 1,25(OH) 2 D 3 impaired the carcinogenesis process in some cases [Wood et al, 1983;Hershberger et al, 1999;Kensler et al, 2000] but it did not alter [Pence et al, 1991] or even facilitated the transformation process in other studies [Wood et al, 1985]. In VDR(À/À) mice, an enhanced sensitivity to chemically induced skin carcinogenesis has been described [Zinser et al, 2002].…”

Section: Discussionmentioning

confidence: 99%

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes

Haes

Garmyn

Carmeliet

et al. 2004

J of Cellular Biochemistry

View full text Add to dashboard Cite

We previously reported that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] protects primary human keratinocytes against ultraviolet (UV)B-induced apoptosis. Here, we confirmed the anti-apoptotic effect of 1,25(OH)2D3 in keratinocytes, using cisplatin and doxorubicin as apoptotic triggers. We further showed that 1,25(OH)2D3 activates two survival pathways in keratinocytes: the MEK/extracellular signal regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. Activation of ERK and Akt by 1,25(OH)2D3 was transient, required a minimal dose of 10(-9) M and could be blocked by actinomycin D and cycloheximide. Moreover, inhibition of Akt or ERK activity with respectively a PI-3K inhibitor (LY294002) or MEK inhibitors (PD98059, UO126), partially or totally suppressed the anti-apoptotic capacity of 1,25(OH)2D3. Finally, 1,25(OH)2D3 changed the expression of different apoptosis regulators belonging to the Bcl-2 family. Indeed, 1,25(OH)2D3 treatment increased levels of the anti-apoptotic protein Bcl-2 and decreased levels of the pro-apoptotic proteins Bax and Bad in a time- and dose-dependent way. Induction of Bcl-2 by 1,25(OH)2D3 was further shown to be mediated by ERK and, to a lesser extent, by Akt. In conclusion, 1,25(OH)2D3 clearly protects keratinocytes against apoptosis (1) by activating the MEK/ERK and the PI-3K/Akt survival pathways and (2) by increasing the Bcl-2 to Bax and Bad ratio.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes

Haes

Garmyn

Carmeliet

et al. 2004

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…Similar to skin papilloma formation in mice, the causative factor of AKs is believed to be chronic/long-term UVR exposure. Previous studies have supported a protective role for 1,25 (OH) 2 D 3 and some related analogues in response to chemical-induced carcinogenesis, also initiated through papilloma formation (34,35).…”

Section: Introductionmentioning

confidence: 89%

1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation–Induced Skin Carcinogenesis

Dixon

Norman

Sequeira

et al. 2011

Cancer Prevention Research

107

153

View full text Add to dashboard Cite

Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1a,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH) 2 D 3 and 1a,25(OH) 2 -lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH) 2 D 3 and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25 (OH) 2 D 3 and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.

show abstract

“…The presence of both the 1-a and the 25-hydroxyl groups is generally thought to be essential for effective binding of the 1,25(OH) 2 D 3 ligand to the VDR (25). It has been reported that the newly synthesized hybrid analogue QW-1624F2-2 (QW; prepared by incorporating the calcium ablating 1-hydroxymethyl alteration along with the potentiating C, D ring 16-unsaturation, side chain 24,24-difluorination, and 26,27-homologation) has potent antiproliferative effects in a skin tumor models (26,27), indicating that growth inhibition may not require the 1-a and 25-dihydroxy groups (28). The side chain group may be binding to the nuclear VDR as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of natural 1,25(OH) 2 D 3 (29).…”

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis

Cited by 36 publications

References 19 publications

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes

1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation–Induced Skin Carcinogenesis

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

Contact Info

Product

Resources

About

Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis

Cited by 36 publications

References 19 publications

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D3 in primary human keratinocytes

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D3 in primary human keratinocytes

1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation–Induced Skin Carcinogenesis

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

Contact Info

Product

Resources

About

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes

Molecular pathways involved in the anti‐apoptotic effect of 1,25‐dihydroxyvitamin D₃ in primary human keratinocytes