Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells

Abstract

Summary We investigated the effects of all-trans retinoic acid (ATRA) and fenretinide (4-HPR) on c-erbB-2 expression in SK-BR-3, and MCF-7 breast cancer cells and on the growth, differentiation, apoptosis and cisplatin (CDDP) sensitivity of SK-BR-3 cells. It has been reported that oestrogen inhibits c-erbB-2 in oestrogen receptor-positive breast cancer cells. Using ELISA, Westem and Northem analysis we have demonstrated that ATRA and 4-HPR exert similar effects down-regulating c-erbB-2 protein and mRNA in c-erbB-2-overexpressing SK-BR-3 and BT-474 and in normally expressing MCF-7 cells. Both retinoids inhibit SK-BR-3 cell growth. ATRA induces cellular enlargement and flattening, suggesting epithelial differentiation. 4-HPR causes nuclear and cytoplasmic condensation, DNA fragmentation and externalization of phosphabdylserine, indicating apoptosis. c-erbB-2 expression/activity has been linked to sensitivity against CDDP. Therefore, combinations of ATRA or 4-HPR with CDDP were tested for their anti-proliferative activity. Retinoid-conditioned cells were either exposed to retinoid and CDDP (schedule 1, 'continuous retinoid treatment') or to CDDP alone (schedule II, 'retinoid pretreatment'). This retinoid-conditioning followed by CDDP ± retinoid yields stronger growth inhibition compared with unconditioned cells, which were exposed to CDDP ± retinoid (schedule 111, 'no retnoid pretreatment'). The inefficacy of schedule Ill indicates that retioidconditioning is essential for the improvement of the antiproliferative effect. The interactions in schedules I and II are synergistic for ATRA and CDDP, but slightly antagonistic for 4-HPR and CDDP. However, 4-HPR + CDDP is more effective in growth inhibition than each drug alone.

Overexpression of ErbB2 in cancer and ErbB2-targeting strategies

“…Interestingly, all-trans retinoic acid (ATRA) and fenretinide (4-HPR) have been shown to downregulate ErbB2 protein and mRNA in ErbB2-overexpressing SKBR3 and BT474 breast cancer cells as well as in MCF-7 cells that express lower levels of ErbB2. Moreover, 4-HPR plus cisplatin has been shown to be more e ective in inhibiting the growth of ErbB2-overexpressing cells than either agent alone (Grunt et al, 1998). Recently, retinoic analogues were also shown to delay mammary tumor development in cneu transgenic mice (Rao et al, 1999).…”

Retinoic Acid Down-Regulates Aldehyde Dehydrogenase and Increases Cytotoxicity of 4-Hydroperoxycyclophosphamide and Acetaldehyde

“…However, few previous studies reported such effects of retinoic acid on other cytotoxic drugs, including cisplatin, etoposide, paclitaxel, and gemcitabine (Formelli and Cleris, 1993;Shalinsky et al, 1996;Grunt et al, 1998;Kalemkerian and Ou, 1999;Pettersson et al, 2001). The basis for those studies was the known antitumor effects of retinoic acids.…”

N-(4-Hydroxyphenyl)-Retinamide Selectively Increases All-<i>Trans</i> Retinoic Acid Inhibitory Effects in <i>HER2/neu</i>-Overexpressing Breast Cancer Cells

“…Laboratory results demonstrated that 4HPR increases the sensitivity of breast cancer cells to tamoxifen, interferon-ß and cisplatinum [14,15,18]. Here, we demonstrate that 4HPR, at a pharmacologically achievable dose, which is approximately 1 ÌM [21], can effectively sensitize HER2/neu-overexpressing breast cancer cells to ATRA.…”

“…4HPR has been shown to repress HER2/neu expression [16,17]. By suppressing the expression of HER2/neu, 4HPR increased the sensitivity of HER2/neu-overexpressing breast cancer cells to cisplatinum [18]. Here we determine whether 4HPR, by suppressing HER2/neu expression, could sensitize breast cancer cells to ATRA.…”