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Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice.

Guillermo RF, Zhang X, Kaushik RS, Zeman D, Ahmed SA, Khalifa S, Fahmy H, Dwivedi C - Mar Drugs (2012)

Bottom Line: Weight gain and any signs of toxicity were also closely monitored.The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose.The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA. Ruth.Guillermo@sdstate.edu

ABSTRACT
Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm(2) UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm(2). This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 h before UVB radiation (30 mJ/cm(2)). The last group of animals received 60 μg SD/200 μL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

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Effects of SD treatment on PCNA positive cells in SKH-1 mice. SD inhibited UVB-induced PCNA expression in the mice skin. All skin samples were collected at the end of the experiment and skins from four random animals per group were used for preparing the sections and four panels from each slide were analyzed. Photographs were taken at 200× and the numbers of positively stained cells were counted. The PCNA staining appears dark brown.
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marinedrugs-10-02111-f006: Effects of SD treatment on PCNA positive cells in SKH-1 mice. SD inhibited UVB-induced PCNA expression in the mice skin. All skin samples were collected at the end of the experiment and skins from four random animals per group were used for preparing the sections and four panels from each slide were analyzed. Photographs were taken at 200× and the numbers of positively stained cells were counted. The PCNA staining appears dark brown.

Mentions: Skin exposure to UVB radiation enhances the proliferation potential of skin cells, reflected in an increase on PCNA positive cells in the epidermis and dermis [31]. Besides causing a significant reduction in the average number of tumors per mouse (Figure 3), SD treatment under all three doses resulted in a reduction in the number of PCNA-positive cells in the skin sections as compared to the control group (acetone treated), seen in Figure 5. Reductions in the number of PCNA positive cells were 16%, 41% and 53.6% for the 30, 45 and 60 μg SD treated groups, respectively. Skin sections from the 60 μg SD group presented a significantly lower number of PCNA positive cells (P < 0.05) compared to the control group (UVB exposed and acetone treated), seen in Figure 6. In these experiments all skin samples for PCNA staining were collected at the end of the experiment. For a clear understanding of SD chemopreventive effects it would be necessary to assess its effects at earlier points in the experiment as well. In addition to PCNA, there are several early molecular biomarkers such as thymine dimers, apoptosis, cyclin D1, p53 and p21 that should be target for evaluation in future studies assessing the skin cancer chemopreventive effects of SD.


Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice.

Guillermo RF, Zhang X, Kaushik RS, Zeman D, Ahmed SA, Khalifa S, Fahmy H, Dwivedi C - Mar Drugs (2012)

Effects of SD treatment on PCNA positive cells in SKH-1 mice. SD inhibited UVB-induced PCNA expression in the mice skin. All skin samples were collected at the end of the experiment and skins from four random animals per group were used for preparing the sections and four panels from each slide were analyzed. Photographs were taken at 200× and the numbers of positively stained cells were counted. The PCNA staining appears dark brown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475277&req=5

marinedrugs-10-02111-f006: Effects of SD treatment on PCNA positive cells in SKH-1 mice. SD inhibited UVB-induced PCNA expression in the mice skin. All skin samples were collected at the end of the experiment and skins from four random animals per group were used for preparing the sections and four panels from each slide were analyzed. Photographs were taken at 200× and the numbers of positively stained cells were counted. The PCNA staining appears dark brown.
Mentions: Skin exposure to UVB radiation enhances the proliferation potential of skin cells, reflected in an increase on PCNA positive cells in the epidermis and dermis [31]. Besides causing a significant reduction in the average number of tumors per mouse (Figure 3), SD treatment under all three doses resulted in a reduction in the number of PCNA-positive cells in the skin sections as compared to the control group (acetone treated), seen in Figure 5. Reductions in the number of PCNA positive cells were 16%, 41% and 53.6% for the 30, 45 and 60 μg SD treated groups, respectively. Skin sections from the 60 μg SD group presented a significantly lower number of PCNA positive cells (P < 0.05) compared to the control group (UVB exposed and acetone treated), seen in Figure 6. In these experiments all skin samples for PCNA staining were collected at the end of the experiment. For a clear understanding of SD chemopreventive effects it would be necessary to assess its effects at earlier points in the experiment as well. In addition to PCNA, there are several early molecular biomarkers such as thymine dimers, apoptosis, cyclin D1, p53 and p21 that should be target for evaluation in future studies assessing the skin cancer chemopreventive effects of SD.

Bottom Line: Weight gain and any signs of toxicity were also closely monitored.The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose.The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA. Ruth.Guillermo@sdstate.edu

ABSTRACT
Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm(2) UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm(2). This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 h before UVB radiation (30 mJ/cm(2)). The last group of animals received 60 μg SD/200 μL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

Show MeSH
Related in: MedlinePlus