afimoxifene and Colorectal-Neoplasms

Antiestrogen tamoxifen (Tam) is the most prescribed drug for the treatment of estrogen receptor (ER)-positive breast cancers. It is also used in long-term clinical trials with encouraging preliminary results as a chemopreventive agent for breast cancer. The effect of Tam on ER-negative cancers, however, is unclear. Here we reported that paclitaxel and 4-hydroxytamoxifen (4-HT) have a synergistic cytotoxic effect on the ER-negative colon cancer cell line HCT15, which is refractory to paclitaxel alone. Our results showed that 4-HT at submicromolar concentrations effectively enhanced the antiproliferative effect of paclitaxel. In addition, at 1/10 of the paclitaxel concentrations used for HCT15, 4-HT and paclitaxel also showed synergistic effect on NCI H460, an ER-negative lung cancer cell line. For both cell lines, the effective concentration for paclitaxel to inhibit cell growth was 1 log lower in the combination treatment than the concentration used in the single treatment. Cell cycle analysis showed that the combination of paclitaxel and 4-HT increased the G2/M population and resulted in the increase of apoptosis in both cell lines. Enhanced early release of cytochrome c from mitochondria may be the apoptotic pathway activated in the combination treatment in HCT15 cells.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Large Cell; Cell Division; Colorectal Neoplasms; Cytochrome c Group; Drug Synergism; Drug Therapy, Combination; Estrogen Receptor Modulators; G2 Phase; Humans; Lung Neoplasms; Mitochondria; Mitosis; Paclitaxel; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured

The authors studied the effect of serial concentrations of estradiol, 4-hydroxytamoxifen with estradiol, and 5-dihydrotestosterone on cell lines derived from human gastric and colorectal cancers. Significant stimulation of the gastric and 2 colorectal cell lines occurred at physiologic concentrations of estradiol. Addition of the active metabolite of the estrogen-receptor blocker/partial-agonist 4-hydroxytamoxifen had a stimulating effect on the growth rate of the gastric cell lines. The androgen, 5-dihydrotestosterone, had a modest inhibitory effect on the two gastric cell lines and two of the colorectal cell lines, and a stimulating effect on two further cell lines.

Topics: Cell Line; Cholesterol; Colorectal Neoplasms; Dihydrotestosterone; Estradiol; Gonadal Steroid Hormones; Humans; Stomach Neoplasms; Tamoxifen