Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells

Abstract

Abstract.We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor e2f1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide.

HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro

“…To generate bicalutamide-resistant cells and enzalutamide-resistant cells, the LNCaP cells, one of the androgen-dependent prostate cancer cell strains, were treated with enzalutamide (10 μ M) ( 32 ) and bicalutamide (10 μ M) (Selleck Chemicals, Houston, TX, USA), respectively for at least 6 months. For the generation of bicalutamide-resistant (Bica-R) cells, the cells were first cultured with 1 μ M ( 33 ), or 5, 10 or 25 μ M ( 34 ) bicalutamide, respectively. We found that the concentration of 1 μ M bicalutamide had almost no effect on the LNCaP cells, and the concentration of 25 μ M bicalutamide killed too many cells to induce the cells continually (data not shown).…”

Substitution of anti-androgens and tegafur-uracil combination therapy for castration-resistant prostate cancer: Results of a multi-center randomized phase II study

“…The majority of patients were switched from bicalutamide to flutamide after they relapsed from the initial hormonal therapy in this study. We recently established a bicalutamide-resistant prostate cancer subline, CDX25R, and demonstrated that the combined treatment of 5-FU and hydroxyflutamide (OH-flutamide), the active metabolite of flutamide, had a synergistic effect on CDX25R cells (21). In addition, we found that OH-flutamide decreased the expression of the E2F1 transcription factor followed by a decreased TS expression in CDX25R cells as the underlying mechanism.…”

Updates on Overcoming Bicalutamide Resistance: A Glimpse into Resistance to a Novel Antiandrogen

“…The suppression of downstream genes such as transcription factor E2F1 and thymidylate synthase was identified as the key driver of inhibition of the growth of resistant cells. 26…”

“…In one study, a combination of flutamide with a chemotherapy agent, 5-fluorouracil, which is an analogue of a pyrimidine base, was capable of inducing apoptosis following an arrest in DNA biosynthesis in bicalutamide-resistant cells. The suppression of downstream genes such as transcription factor E2F1 and thymidylate synthase was identified as the key driver of inhibition of the growth of resistant cells …”