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20(S)-protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer.

Cao B, Qi Y, Yang Y, Liu X, Xu D, Guo W, Zhan Y, Xiong Z, Zhang A, Wang AR, Fu X, Zhang H, Zhao L, Gu J, Dong Y - PLoS ONE (2014)

Bottom Line: We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs.PPD treatment resulted in a suppression of ligand-independent AR transactivation.This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Jilin University, Changchun, China; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.

ABSTRACT
Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.

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PPD inhibition of the growth of castration-resistant 22Rv1 xenograft tumors.22Rv1 cells were inoculated into castrated nude mice. When the tumors reached ∼100 mm3, the mice were treated with 40 mg/kg PPD through oral gavage 6 days per week (n = 11). A. Mean tumor volumes. B. Individual tumor weight at the conclusion of the experiment. C. Mean mouse body weights. D. Mean serum PSA level determined by ELISA, normalized by tumor weights, at the conclusion of the study. *, P<0.05 from the control group. Error bars, SEM.
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pone-0111201-g005: PPD inhibition of the growth of castration-resistant 22Rv1 xenograft tumors.22Rv1 cells were inoculated into castrated nude mice. When the tumors reached ∼100 mm3, the mice were treated with 40 mg/kg PPD through oral gavage 6 days per week (n = 11). A. Mean tumor volumes. B. Individual tumor weight at the conclusion of the experiment. C. Mean mouse body weights. D. Mean serum PSA level determined by ELISA, normalized by tumor weights, at the conclusion of the study. *, P<0.05 from the control group. Error bars, SEM.

Mentions: We next assessed the ability of PPD, in comparison with the next-generation antiandrogen enzalutamide, to inhibit the growth of prostate tumors that are already castration resistant by using the 22Rv1 xenograft model. 22Rv1 cells were inoculated into the right dorsal flank of castrated male nude mice. Administration of 40 mg/kg PPD or 10 or 30 mg/kg enzalutamide through oral gavage 6 days per week was initiated when the tumors reach ∼100 mm3. As shown in Figure 5A, PPD significantly inhibited the growth of the 22Rv1 tumors. At the conclusion of the experiment, the average weight of the tumors was 0.35 g in the PPD group, but 0.54 g in the control group, indicating ∼35% inhibition of tumor growth by PPD (Figure 5B). This was also associated with ∼50% decline in serum PSA levels (Figure 5D) as well as a significant decrease in AR immunostaining signal detected using a pan-AR antibody (Figure 6A) and the number of mitoses (Figure 6B) in the tumors. Western blot analysis further showed PPD downregulation of both AR-FL and AR-Vs in the tumors (Figure 6C). PPD did not cause decrease in the body weights of the mice (Figure 5C) or apparent histopathological change of the tumors (Figure 6D).


20(S)-protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer.

Cao B, Qi Y, Yang Y, Liu X, Xu D, Guo W, Zhan Y, Xiong Z, Zhang A, Wang AR, Fu X, Zhang H, Zhao L, Gu J, Dong Y - PLoS ONE (2014)

PPD inhibition of the growth of castration-resistant 22Rv1 xenograft tumors.22Rv1 cells were inoculated into castrated nude mice. When the tumors reached ∼100 mm3, the mice were treated with 40 mg/kg PPD through oral gavage 6 days per week (n = 11). A. Mean tumor volumes. B. Individual tumor weight at the conclusion of the experiment. C. Mean mouse body weights. D. Mean serum PSA level determined by ELISA, normalized by tumor weights, at the conclusion of the study. *, P<0.05 from the control group. Error bars, SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222907&req=5

pone-0111201-g005: PPD inhibition of the growth of castration-resistant 22Rv1 xenograft tumors.22Rv1 cells were inoculated into castrated nude mice. When the tumors reached ∼100 mm3, the mice were treated with 40 mg/kg PPD through oral gavage 6 days per week (n = 11). A. Mean tumor volumes. B. Individual tumor weight at the conclusion of the experiment. C. Mean mouse body weights. D. Mean serum PSA level determined by ELISA, normalized by tumor weights, at the conclusion of the study. *, P<0.05 from the control group. Error bars, SEM.
Mentions: We next assessed the ability of PPD, in comparison with the next-generation antiandrogen enzalutamide, to inhibit the growth of prostate tumors that are already castration resistant by using the 22Rv1 xenograft model. 22Rv1 cells were inoculated into the right dorsal flank of castrated male nude mice. Administration of 40 mg/kg PPD or 10 or 30 mg/kg enzalutamide through oral gavage 6 days per week was initiated when the tumors reach ∼100 mm3. As shown in Figure 5A, PPD significantly inhibited the growth of the 22Rv1 tumors. At the conclusion of the experiment, the average weight of the tumors was 0.35 g in the PPD group, but 0.54 g in the control group, indicating ∼35% inhibition of tumor growth by PPD (Figure 5B). This was also associated with ∼50% decline in serum PSA levels (Figure 5D) as well as a significant decrease in AR immunostaining signal detected using a pan-AR antibody (Figure 6A) and the number of mitoses (Figure 6B) in the tumors. Western blot analysis further showed PPD downregulation of both AR-FL and AR-Vs in the tumors (Figure 6C). PPD did not cause decrease in the body weights of the mice (Figure 5C) or apparent histopathological change of the tumors (Figure 6D).

Bottom Line: We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs.PPD treatment resulted in a suppression of ligand-independent AR transactivation.This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Jilin University, Changchun, China; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.

ABSTRACT
Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.

Show MeSH
Related in: MedlinePlus