20(S)-protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer.
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.
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.
Bo
B
Cao
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Yanfeng
Y
Qi
College of Life Sciences, Jilin University, Changchun, China.
Yan
Y
Yang
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Xichun
X
Liu
College of Life Sciences, Jilin University, Changchun, China.
Duo
D
Xu
College of Life Sciences, Jilin University, Changchun, China.
Wei
W
Guo
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Yang
Y
Zhan
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Zhenggang
Z
Xiong
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Allen
A
Zhang
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Alun R
AR
Wang
College of Life Sciences, Jilin University, Changchun, China.
Xueqi
X
Fu
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, United States of America.
Haitao
H
Zhang
College of Basic Medical Sciences, Jilin University, Changchun, China.
Lijing
L
Zhao
College of Life Sciences, Jilin University, Changchun, China.
Jingkai
J
Gu
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; National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, China.
Yan
Y
Dong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012502:Sapogenins / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011944:Receptors, Androgen; D012502:Sapogenins; C062916:protopanaxadiol