Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity

• Published in: Molecular cancer therapeutics Vol. 15; no. 6; pp. 1353 - 1363
• Main Authors: Udayakumar, Thirupandiyur S, Stoyanova, Radka, Shareef, Mohammed M, Mu, Zhaomei, Philip, Sakhi, Burnstein, Kerry L, Pollack, Alan
• Format: Journal Article
• Language: English
• Published: United States 01.06.2016
• Subjects: Activating Transcription Factor 3 - metabolism; Androgen Antagonists - administration & dosage; Androgen Antagonists - pharmacology; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Synergism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Mice; Neoplasm Transplantation; Phospholipid Ethers - administration & dosage; Phospholipid Ethers - pharmacology; Promoter Regions, Genetic - drug effects; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Up-Regulation; Xenograft Model Antitumor Assays
• DOI: 10.1158/1535-7163.MCT-15-0332
• ISSN: 1535-7163

Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose-dependent decrease in AKT activity, but did not affect the expression of total AKT in either cell line. Furthermore, edelfosine treatment inhibited the expression of androgen receptor (AR) and was associated with an increase in activating transcription factor 3 (ATF3) expression levels, a stress response gene and a negative regulator of AR transactivation. ATF3 binds to AR after edelfosine + AD and represses the transcriptional activation of AR as demonstrated by PSA promoter studies. Knockdown of ATF3 using siRNA-ATF3 reversed the inhibition of PSA promoter activity, suggesting that the growth inhibition effect of edelfosine was ATF3 dependent. Moreover, expression of AR variant 7 (ARv7) and TMPRSS2-ERG fusion gene were greatly inhibited after combined treatment with AD and edelfosine in VCaP cells. In vivo experiments using an orthotopic LNCaP model confirmed the antitumor effects of edelfosine + AD over the individual treatments. A significant decrease in tumor volume and PSA levels was observed when edelfosine and AD were combined, compared with edelfosine alone. Edelfosine shows promise in combination with AD for the treatment of prostate cancer patients. Mol Cancer Ther; 15(6); 1353-63. ©2016 AACR.