Anti-proliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor-positive clinical breast cancer.

Selective estrogen receptor modulators and a combination of mechanistically distinct chemotherapeutic agents represent conventional therapeutic interventions for estrogen receptor-positive (ER+) clinical breast cancer. Long-term treatment with these agents is associated with acquired tumor resistance and other adverse side effects that impact on patient compliance. Herbal medicines are being widely used in complementary and alternative medicine. However, long-term safety and efficacy of the use of herbal medicines, as well as their interaction with conventional endocrine and chemotherapeutic drug regimens remain largely unknown. The present study utilized a human cell culture model for ER+ clinical breast cancer to examine the potential therapeutic efficacy of an aqueous extract prepared from the fruit of popular Chinese herb Cornus officinalis (CO), also known as Fructus cornii. The human mammary carcinoma-derived MCF-7 cell line represented the model. Status of anchorage-independent growth and cellular metabolism of 17ß-estradiol (E2) represented the quantitative end-point biomarkers for efficacy. MCF-7 cells adapted for growth in serum-depleted medium (0.7% serum, <1 nM E2) retained their endocrine responsiveness as evidenced by growth promotion by physiological levels of E2, and growth inhibition by the selective ER modulator tamoxifen at the clinically achievable concentrations. Treatment of MCF-7 cells with CO resulted in inhibition of E2-stimulated growth in a dose-dependent manner. Similarly, CO treatment also produced a dose-dependent progressive reduction in the number of anchorage-independent colonies, indicating effective reduction of the carcinogenic risk. Treatment of MCF-7 cells with CO at a maximally effective cytostatic concentration resulted in a 5.1-fold increase in the formation of the anti-prolifertive E2 metabolite 2-hydoxyestrone (2-OHE1), a 63.6% decrease in the formation of the pro-mitogenic metabolite 16α-hydroxestrone (16-αOHE1) and a 9.1% decrease in the formation of mitogenically inert metabolite estrone (E3). These alterations led to a 14.5-fold increase in the 2-OHE1:16α-OHE1, and a 3.3-fold increase in the E3:16α-OHE1 ratios. These data validate a rapid cell culture-based mechanistic approach to prioritize efficacious herbal medicinal products for long-term animal studies and future clinical trials on ER+ clinical breast cancer.

Growth inhibition of estrogen receptor positive human breast cancer cells by Taheebo from the inner bark of Tabebuia avellandae tree.

Selective estrogen receptor (ER) modulators are used as a therapy for ER+ clinical breast cancer, but they exhibit adverse effects. Herbal medicines may provide an alternative or complementary approach. Taheebo, extracted from the inner bark of the Tabebuia avellandae tree found in the Brazilian Amazon, exhibits selective anti-proliferative effects in carcinoma cell lines. The present study identifies the mechanistic leads for the inhibitory effects of Taheebo. Human breast carcinoma derived ER+MCF-7 cells were used as the model. Aqueous extract of Taheebo was the test compound. Cell cycle analysis, clonogenic assay, and global gene expression profiles were the quantitative parameters. Taheebo treatment resulted in a dose/time-dependent growth inhibition (S phase arrest, reduced clonogeneticity) and initiation of apoptosis (chromatin condensation). A 6-h treatment with 1.5 mg/ml Taheebo modulated the gene expression of G2 specific cyclin B1 (-2.0-fold); S phase specific PCNA (-2.0-fold) and OKL38 (+11.0-fold); apoptosis specific GADD-45 family (+1.9-5.4-fold), Caspases (+1.6-1.7-fold), BCL-2 family (-1.5-2.5-fold), estrogen responsive ESR1 (-1.5-fold), and xeno-biotic metabolism specific CYP 1A1 (+19.8 fold) and CYP 1B1 (+7.9-fold). The anti-proliferative effects of Taheebo correlate with down-regulated cell cycle regulatory and estrogen responsive genes, and up-regulated apoptosis specific and xeno-biotic metabolism specific genes. These data validate a rapid mechanistic approach to prioritize efficacious herbal medicines, thereby complementing the existing endocrine therapy for breast cancer.