Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer.
Relapse of prostate cancer after androgen ablation therapy is hormone-refractory, with continued tumor growth being dependent on the androgen receptor (AR). E2F-1, a regulator of cell proliferation and viability, reportedly plays a role in the development of hormone-refractory prostate cancer. Thymoquinone is a component of Nigella sativa, an herb used for thousands of years for culinary and medicinal purposes in Asian and Middle Eastern countries and has been reported to have an antineoplastic effect both in vitro and in vivo. We observed that thymoquinone inhibited DNA synthesis, proliferation, and viability of cancerous (LNCaP, C4-B, DU145, and PC-3) but not noncancerous (BPH-1) prostate epithelial cells by down-regulating AR and E2F-1. In LNCaP cells, this was associated with a dramatic increase in p21(Cip1), p27(Kip1), and Bax. Thymoquinone blunted progression of synchronized LNCaP cells from G1 to S phase, with a concomitant decrease in AR and E2F-1 as well as the E2F-1-regulated proteins necessary for cell cycle progression. In a xenograft prostate tumor model, thymoquinone inhibited growth of C4-2B-derived tumors in nude mice. This in vivo suppression of tumor growth, as with C4-2B cell growth in culture, was associated with a dramatic decrease in AR, E2F-1, and cyclin A as determined by Western blot of tissue extracts. Tissue immunohistochemical staining confirmed a marked reduction in E2F-1 and showed induction of apoptosis on terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. These findings show that thymoquinone suppresses the expression of AR and E2F-1 necessary for proliferation and viability of androgen-sensitive as well as androgen-independent prostate cancer cells both in vitro and in vivo and, moreover, produced no noticeable side effects in mice. We conclude that thymoquinone, a naturally occurring herbal product, may prove to be effective in treating hormone-sensitive as well as hormone-refractory prostate cancer. Furthermore, because of its selective effect on cancer cells, we believe that thymoquinone can also be used safely to help prevent the development of prostate cancer.
Kaseb
Ahmed O
AO
Department of Hematology/Oncology, Henry Ford Hospital, MI 458202, USA.
Chinnakannu
Kannagi
K
Chen
Di
D
Sivanandam
Arun
A
Tejwani
Sheela
S
Menon
Mani
M
Dou
Q Ping
QP
Reddy
G Prem-Veer
GP
D059002:Androgen Receptor Antagonists; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016196:S Phase / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D059002:Androgen Receptor Antagonists; D016227:Benzoquinones; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C003466:thymoquinone