20(S)-protopanaxadiol Inhibition of Progression and Growth of Castration-resistant Prostate Cancer

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Nov 7

PMID 25375370

Citations 21

Authors

Bo Cao

Yanfeng Qi

Yan Yang

Xichun Liu

Duo Xu

Wei Guo

Yang Zhan

Zhenggang Xiong

Allen Zhang

Alun R Wang

Xueqi Fu

Haitao Zhang

Lijing Zhao

Jingkai Gu

Yan Dong

Affiliations

Soon will be listed here.

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.

Citing Articles

Synergistic Strategies for Castration-Resistant Prostate Cancer: Targeting AR-V7, Exploring Natural Compounds, and Optimizing FDA-Approved Therapies.

Rahman M, Akter K, Ahmed K, Maharub Hossain Fahim M, Aktary N, Park M Cancers (Basel). 2024; 16(16).

PMID: 39199550 PMC: 11352813. DOI: 10.3390/cancers16162777.

Rare ginsenosides: A unique perspective of ginseng research.

Fan W, Fan L, Wang Z, Mei Y, Liu L, Li L J Adv Res. 2024; 66:303-328.

PMID: 38195040 PMC: 11674801. DOI: 10.1016/j.jare.2024.01.003.

Pharmacokinetics and pharmacodynamics of Rh2 and aPPD ginsenosides in prostate cancer: a drug interaction perspective.

Ben-Eltriki M, Shankar G, Guns E, Deb S Cancer Chemother Pharmacol. 2023; 92(6):419-437.

PMID: 37709921 DOI: 10.1007/s00280-023-04583-y.

Transcriptome Analysis of the Inhibitory Effects of 20(S)-Protopanaxadiol on NCI-H1299 Non-Small Cell Lung Cancer Cells.

Cong Z, Zhang X, Lv Z, Jiang J, Wang L, Li J Molecules. 2023; 28(15).

PMID: 37570716 PMC: 10421167. DOI: 10.3390/molecules28155746.

Gut Microbiota: Therapeutic Targets of Ginseng Against Multiple Disorders and Ginsenoside Transformation.

Chen Z, Zhang Z, Liu J, Qi H, Li J, Chen J Front Cell Infect Microbiol. 2022; 12:853981.

PMID: 35548468 PMC: 9084182. DOI: 10.3389/fcimb.2022.853981.

References

Narizhneva N, Tararova N, Ryabokon P, Shyshynova I, Prokvolit A, Komarov P . Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer. Cell Cycle. 2009; 8(24):4155-67. PMC: 2896895. DOI: 10.4161/cc.8.24.10316. View

Li Y, Chan S, Brand L, Hwang T, Silverstein K, Dehm S . Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2012; 73(2):483-9. PMC: 3549016. DOI: 10.1158/0008-5472.CAN-12-3630. View

Horoszewicz J, Leong S, Chu T, Wajsman Z, Friedman M, Papsidero L . The LNCaP cell line--a new model for studies on human prostatic carcinoma. Prog Clin Biol Res. 1980; 37:115-32. View

Chen C, Welsbie D, Tran C, Baek S, Chen R, Vessella R . Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004; 10(1):33-9. DOI: 10.1038/nm972. View

Yuan C, Wang C, Wicks S, Qi L . Chemical and pharmacological studies of saponins with a focus on American ginseng. J Ginseng Res. 2011; 34(3):160-7. PMC: 3043615. DOI: 10.5142/jgr.2010.34.3.160. View

Lee N, Yoo S, Kim H, Cho J, Son C . Safety and tolerability of Panax ginseng root extract: a randomized, placebo-controlled, clinical trial in healthy Korean volunteers. J Altern Complement Med. 2012; 18(11):1061-9. PMC: 3501011. DOI: 10.1089/acm.2011.0591. View

Zengerling F, Streicher W, Schrader A, Schrader M, Nitzsche B, Cronauer M . Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells. Int J Mol Sci. 2012; 13(9):11530-11542. PMC: 3472761. DOI: 10.3390/ijms130911530. View

Li X, Liu Z, Xu X, Blair C, Sun Z, Xie J . Kava components down-regulate expression of AR and AR splice variants and reduce growth in patient-derived prostate cancer xenografts in mice. PLoS One. 2012; 7(2):e31213. PMC: 3276576. DOI: 10.1371/journal.pone.0031213. View

Jackson J, Gleave M, Yago V, Beraldi E, Hunter W, Burt H . The suppression of human prostate tumor growth in mice by the intratumoral injection of a slow-release polymeric paste formulation of paclitaxel. Cancer Res. 2000; 60(15):4146-51. View

10.

Li J, Cao B, Liu X, Fu X, Xiong Z, Chen L . Berberine suppresses androgen receptor signaling in prostate cancer. Mol Cancer Ther. 2011; 10(8):1346-56. PMC: 3154574. DOI: 10.1158/1535-7163.MCT-10-0985. View

11.

Sun S, Sprenger C, Vessella R, Haugk K, Soriano K, Mostaghel E . Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010; 120(8):2715-30. PMC: 2912187. DOI: 10.1172/JCI41824. View

12.

Mostaghel E, Marck B, Plymate S, Vessella R, Balk S, Matsumoto A . Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 2011; 17(18):5913-25. PMC: 3184252. DOI: 10.1158/1078-0432.CCR-11-0728. View

13.

Reagan-Shaw S, Nihal M, Ahmad N . Dose translation from animal to human studies revisited. FASEB J. 2007; 22(3):659-61. DOI: 10.1096/fj.07-9574LSF. View

14.

Scher H, Fizazi K, Saad F, Taplin M, Sternberg C, Miller K . Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012; 367(13):1187-97. DOI: 10.1056/NEJMoa1207506. View

15.

Hu R, Lu C, Mostaghel E, Yegnasubramanian S, Gurel M, Tannahill C . Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012; 72(14):3457-62. PMC: 3415705. DOI: 10.1158/0008-5472.CAN-11-3892. View

16.

Locke J, Guns E, Lubik A, Adomat H, Hendy S, Wood C . Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008; 68(15):6407-15. DOI: 10.1158/0008-5472.CAN-07-5997. View

17.

Knudsen K, Scher H . Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009; 15(15):4792-8. PMC: 2842118. DOI: 10.1158/1078-0432.CCR-08-2660. View

18.

Tran C, Ouk S, Clegg N, Chen Y, Watson P, Arora V . Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009; 324(5928):787-90. PMC: 2981508. DOI: 10.1126/science.1168175. View

19.

Cao B, Liu X, Li J, Liu S, Qi Y, Xiong Z . 20(S)-protopanaxadiol-aglycone downregulation of the full-length and splice variants of androgen receptor. Int J Cancer. 2012; 132(6):1277-87. PMC: 3509250. DOI: 10.1002/ijc.27754. View

20.

Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C . In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995; 9(4):401-6. DOI: 10.1038/ng0495-401. View