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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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Enzalutamide did not affect 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 10 or 30 mg/kg enzalutamide through oral gavage 6 days per week (n = 4). 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. Enz, enzalutamide. Neither of the treatment groups showed statistical difference from the control group in any of the endpoints. Error bars, SEM.
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pone-0111201-g007: Enzalutamide did not affect 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 10 or 30 mg/kg enzalutamide through oral gavage 6 days per week (n = 4). 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. Enz, enzalutamide. Neither of the treatment groups showed statistical difference from the control group in any of the endpoints. Error bars, SEM.

Mentions: Interestingly, enzalutamide, at neither dose, was able to inhibit the growth of 22Rv1 tumors (Figure 7A), suppress serum PSA levels in the mice (Figure 7D), inhibit mitosis (Figure 8A), or cause apparent histopathological change of the 22Rv1 tumors (Figure 8B). At the conclusion of the experiment, there was a trend of decrease in tumor weights with increasing dose of enzalutamide (Figure 7B). However, the decrease was not statistically significant, possibly due to the small sample size of the experiment. Nonetheless, the decrease observed with 10 mg/kg enzalutamide, the most commonly-used dose of enzalutamide that is effective against castration-resistant LNCaP xenograft models [27], [51], [52], was rather marginal. Taken together, the data suggest the potential of using PPD to inhibit the growth of CRPC.


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)

Enzalutamide did not affect 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 10 or 30 mg/kg enzalutamide through oral gavage 6 days per week (n = 4). 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. Enz, enzalutamide. Neither of the treatment groups showed statistical difference from the control group in any of the endpoints. Error bars, SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111201-g007: Enzalutamide did not affect 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 10 or 30 mg/kg enzalutamide through oral gavage 6 days per week (n = 4). 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. Enz, enzalutamide. Neither of the treatment groups showed statistical difference from the control group in any of the endpoints. Error bars, SEM.
Mentions: Interestingly, enzalutamide, at neither dose, was able to inhibit the growth of 22Rv1 tumors (Figure 7A), suppress serum PSA levels in the mice (Figure 7D), inhibit mitosis (Figure 8A), or cause apparent histopathological change of the 22Rv1 tumors (Figure 8B). At the conclusion of the experiment, there was a trend of decrease in tumor weights with increasing dose of enzalutamide (Figure 7B). However, the decrease was not statistically significant, possibly due to the small sample size of the experiment. Nonetheless, the decrease observed with 10 mg/kg enzalutamide, the most commonly-used dose of enzalutamide that is effective against castration-resistant LNCaP xenograft models [27], [51], [52], was rather marginal. Taken together, the data suggest the potential of using PPD to inhibit the growth of CRPC.

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