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.