20(S)-Protopanaxadiol Inhibition of Progression and Growth of Castration-Resistant Prostate Cancer

Cao, Bo; Qi, Yingyong; Yang, Yan; Liu, Xichun; Xu, Dongmei; Guo, Wei; Yang, Zhan; Xiong, Zhenggang; Zhang, Allen; Wang, Alun R.; Fu, Xueqi; Zhang, Haitao; Zhao, Lijing; Gu, Jingkai; Dong, Yan

doi:10.1371/journal.pone.0111201

Cited by 36 publications

(34 citation statements)

References 53 publications

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“…The C4‐2b cell line, a murine bone metastatic derivative of LNCaP, has a nearly identical AR status, but showed higher expression of AR variants . 22Rv1 is known to have various AR variants including AR‐V7, and is also known to be resistant to enzalutamide treatment . VCaP cells have amplified expression of wild type AR and also have detectable levels of AR‐V7 .…”

Section: Resultsmentioning

confidence: 99%

Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer

Lee

Hong

Kang

et al. 2018

Intl Journal of Cancer

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Prostate cancer can be controlled by androgen-hormone treatment until the cancer becomes refractory. It is believed that hormone sensitivity is largely dependent on androgen receptor (AR) activity. Here, we found the histone demethylase KDM7A which demethylates histone H3K27 to be overexpressed in enzalutamide resistant castration-resistant prostate cancer cell line C4-2b, and investigated the molecular mechanism whereby androgen receptor activity is regulated by KDM7A. We engineered AR-positive LNCaP cells to stably express a short-hairpin RNA against KDM7A mRNA from a lentiviral vector. By measuring AR downstream gene expression after androgen stimulation, we found that a KDM7A-deficient cell line showed lower AR downstream gene expression compared to a control cell. KDM7A knock-down in LNCaP cell line caused decreased cell proliferation. Western blot analysis with modified-histone antibody revealed that the KDM7A-knock-down LNCaP cell line had increased H3K27 di-methylation. We confirmed KDM7A binding on AR target-gene promoters after hormone stimulation in chromatin-immunoprecipitation experiments. And increased H3K27 di-methylation was observed in KDM7A knock-down LNCaP stable cell. Treatment with KDM7A inhibitor, TC-E 5002, reduced proliferation and induced apoptosis of prostate cancer cells. Finally, we observed that the KDM7A protein was significantly upregulated in prostate cancer tissue, and that this difference correlated with the Gleason score. These data suggested that KDM7A is potentially a good therapeutic target for prostate cancer drugs and can be used as potentially a good prognostic indicator for prostate cancer and related treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer

Lee

Hong

Kang

et al. 2018

Intl Journal of Cancer

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“…1) is one of aglycones of ginsenosides and has a wide range of pharmacological activities, especially in antitumor and neurological function recovery. [4][5][6][7][8] However, the low bioavailability of ginsenosides (1% for Rb 1 , 3.4% for Rb 2 , 1.9% for Rg 1 ) after oral administration restricts their clinical applications. [9][10][11] Importantly, PPD is the final active component after the absorption of ginsenosides in intestine.…”

mentioning

confidence: 99%

Self-microemulsifying Drug Delivery System Improved Oral Bioavailability of 20(<i>S</i>)-Protopanaxadiol: From Preparation to Evaluation

Wang

et al. 2015

Chem. Pharm. Bull.

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20(S)-Protopanaxadiol (20(S)-PPD)is one type of sapogenin of protopanaxadiols and has a variety of pharmacological activities. In order to improve the dissolution of 20(S)-PPD as well as its oral bioavailability, a self-microemulsifying drug delivery system (SMEDDS) was utilized for 20(S)-PPD preparation. Following the preparation of the 20(S)-PPD SMEDDS, its dissolution, stability, and intestinal absorption in rats were studied, and the pharmacokinetics and optimal dosage after oral administration were evaluated. The dissolution tendency of the SMEDDS in phosphate buffered saline (PBS), 0.1 M HCl and distilled water was consistent. SMEDDS was stable under a condition of high temperature (40°C), high humidity or with strong light irradiation, or within 6 h in artificial digestive tracts. 20(S)-PPD SMEDDS was well-absorbed in all intestinal segments in rats. When the drug concentration was higher than 200 µg/mL or the perfusion flow was faster than 0.5 mL/min, passive diffusion of drug in the duodenum reached a saturated level. In addition, Pglycoprotein inhibitor did not affect the intestinal absorption of 20(S)-PPD SMEDDS. Pharmacokinetic study showed that T max in male rats was shortened significantly, while C max and area under the curve (AUC (0-t) ) were remarkably increased. The relative oral bioavailability of 20(S)-PPD SMEDDS was increased approximately three fold compared with the 20(S)-PPD carboxy methyl cellulose (CMC). 20(S)-PPD SMEDDS (100 mg/mL) was administered by gastric infusion to both mice and rats for 14 d. SMEDDS improved the oral bioavailability of 20(S)-PPD and reduced the necessary drug dosage. 20(S)-PPD SMEDDS could become a promising clinical alternative as an anti-tumor or antidepressant drug.Key words 20(S)-protopanaxadiol; self-microemulsifying drug delivery system; preparation; bioavailability; intestinal absorption; pharmacokinetics Panax ginseng is documented to tonify internal organs, benefit the spirit, suppress the fright as well as improve eyesight and intelligence.1) The long term application also facilitates relaxation and increases life span.2) Various chemical components were distinguished in Panax ginseng, including saponins, volatile oil, polysaccharides, amino acid and polypeptide, and microelements, of which ginsenosides are the main active ingredients, including oleanolic acid (OA), protopanaxadiol (PPD) and protopanaxatriol type (PPT).3) 20(S)-PPD ( Fig. 1) is one of aglycones of ginsenosides and has a wide range of pharmacological activities, especially in antitumor and neurological function recovery. [4][5][6][7][8] However, the low bioavailability of ginsenosides (1% for Rb 1 , 3.4% for Rb 2 , 1.9% for Rg 1 ) after oral administration restricts their clinical applications. 9-11)Importantly, PPD is the final active component after the absorption of ginsenosides in intestine. 12,13)

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“…That is to target AR-FL and AR-Vs. In addition to RA, several other compounds have been shown pre-clinically to reduce the levels of AR-FL and AR-Vs. 34,[48][49][50][51][52][53][54][55][56][57][58] These compounds may serve as an effective antidote to overcoming resistance to androgen deprivation therapy for treatment of CRPC. 1,2 ).…”

Section: Discussionmentioning

confidence: 99%

Raddeanin A down‐regulates androgen receptor and its splice variants in prostate cancer

Xia

Bai

et al. 2019

J Cellular Molecular Medi

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Castration‐resistant progression of prostate cancer is a major cause of prostate cancer mortality, and increased expression and activity of the full‐length and the splice variants of androgen receptor (AR) have been indicated to drive castration resistance. Consequently, there is an urgent need to develop agents that can target both the full‐length and the splice variants of AR for more effective treatment of prostate cancer. In the present study, we showed that raddeanin A (RA), an oleanane‐type triterpenoid saponin, suppresses the transcriptional activities of both the full‐length and the splice variants of AR. This is attributable to their decreased expression as a result of RA induction of proteasome‐mediated degradation and inhibition of the transcription of the AR gene. We further showed the potential of using RA to enhance the growth inhibitory efficacy of docetaxel, the first‐line chemotherapy for prostate cancer. This study identifies RA as a new agent to target both the full‐length and the splice variants of AR and provides a rationale for further developing RA for prostate cancer treatment.

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20(S)-Protopanaxadiol Inhibition of Progression and Growth of Castration-Resistant Prostate Cancer

Cited by 36 publications

References 53 publications

Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer

Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer

Self-microemulsifying Drug Delivery System Improved Oral Bioavailability of 20(<i>S</i>)-Protopanaxadiol: From Preparation to Evaluation

Raddeanin A down‐regulates androgen receptor and its splice variants in prostate cancer

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