Experimental Studies on the Effects of the Combined Use of N-(4-hydroxyphenyl)retinamide (4-HPR) and Tamoxifen (TAM) for Estrogen Receptor (ER)-Negative Breast Cancer

• Published in: Kurume medical journal Vol. 49; no. 1-2; pp. 27 - 33
• Main Author: AOYAMA, YUKO
• Format: Journal Article
• Language: English
• Published: Japan Kurume University School of Medicine 2002
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle - drug effects; Chromatography, Thin Layer; estrogen receptor negative breast cancer; Fenretinide - administration & dosage; Fenretinide - pharmacology; Fenretinide - therapeutic use; G(M3) Ganglioside - metabolism; G2 arrest; Humans; N-(4-hydroxyphenyl)retinamide; Receptors, Estrogen - metabolism; tamoxifen; Tamoxifen - administration & dosage; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Tumor Cells, Cultured
• ISSN: 0023-5679; 1881-2090
• DOI: 10.2739/kurumemedj.49.27

We investigated the effects of combination therapy with N-(4-hydroxyphenyl)retinamide (4-HPR) and tamoxifen (TAM) on estrogen receptor (ER) negative breast cancer, for which no effective supplementary therapy has been established, using the human breast cancer cell line MDA-MB-231. TAM or 4-HPR alone had little antitumor effect, but the combined use of TAM and 4-HPR had a strong cell growth inhibitory effect. Cell cycle analysis by flow cytometry showed an increased frequency of the G2/M phases in the 4-HPR-TAM combination group. Measurement of 3H-TAM incorporation into the cell showed that, compared with the TAM group, the 4-HPR-TAM combination group incorporated about 1.45 times more TAM into the cell. Thin-layer chromatographic analysis of changes in the cell membrane ganglioside GM3 showed a marked increase in GM3 in the 4-HPR-TAM combination group. We speculate that the administration of TAM in the presence of 4-HPR changes the membrane glycolipid GM3, increasing intracellular TAM concentrations, thus exerting antitumor activity. Presumably, during this process, antitumor effects do not induce cell death but arrest the cell cycle in the G2 phase. Thus, the combined use of TAM and 4-HPR inhibited the growth of the ER-negative breast cancer cell line MDA-MB-231. These results suggest that combination therapy with TAM and 4-HPR can be a potent supplementary therapy also for ER-negative patients in clinical practice.