Effects of ALL-trans-retinoic acid and 13-cis-retinoic acid on breast-cancer cell lines: Growth inhibition and apoptosis induction

Toma, Salvatore; Isnardi, L.; Raffo, P; Dastoli, Giuseppe; Francisci, Elena De; Riccardi, Lucia; Palumbo, R.; Bollag, W.

doi:10.1002/(sici)1097-0215(19970304)70:5<619::aid-ijc21>3.0.co;2-6

Cited by 114 publications

(68 citation statements)

References 15 publications

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“…ATRA was found to decrease cell growth of MCF-7 cells (Toma et al, 1997). This was confirmed in the present paper by cytometric data, after DNA content evaluation and BrdU vs DNA dual-parameter measurements.…”

Section: Discussionsupporting

confidence: 89%

All-trans retinoic acid (ATRA)-induced apoptosis is preceded by G1 arrest in human MCF-7 breast cancer cells

Mangiarotti¹,

Danova²,

R³

et al. 1998

Br J Cancer

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In this study the effects of all-trans retinoic acid (ATRA) on cell cycle and apoptosis of MCF-7 human breast cancer cells were investigated to elucidate the mechanisms underlying the antineoplastic potential of this retinoid in breast cancer. The antiproliferative effect of ATRA was evaluated by DNA content measurements and dual-parameter flow cytometry of bromodeoxyuridine (BrdU) incorporation and of the expression of cell cycle-related proteins (Ki-67 as proliferation marker and statin as quiescence marker) vs DNA content. Apoptosis was also studied by flow cytometry of either DNA content or Annexin V labelling. After 10(-6) M ATRA treatment, the fraction of S-phase cells decreased significantly, and cells accumulated in the G0/G1 range of DNA contents. Dual-parameter flow cytograms showed a decrease in the percentage of Ki-67-labelled cells (after 10 days, only 20% of the cells were still positive for Ki-67 compared with 95% in controls), while the fraction of statin-positive cells increased slightly. From 3 days of treatment onwards, apoptosis was found to occur. These results show that ATRA-induced inhibition of MCF-7 cell growth is related to two mechanisms, i.e. the block of cell proliferation, mostly in a pre-S phase, and the induction of apoptosis. These results should be taken into account when attempting to design treatment programmes that associate ATRA with antineoplastic compounds of different cell cycle specificity.

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Section: Discussionsupporting

confidence: 89%

All-trans retinoic acid (ATRA)-induced apoptosis is preceded by G1 arrest in human MCF-7 breast cancer cells

Mangiarotti¹,

Danova²,

R³

et al. 1998

Br J Cancer

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“…Except where otherwise stated, all cells were assessed following 6 days of ATRA/RAMBAs treatments. We point out that several researchers Toma et al, 1997) including us (Patel et al, 2004) have found that induction of several biochemical pathways in most cancer cell line become evident only after 6 days of ATRA/retinoid treatment.…”

Section: Effects Of Rambas On Mcf-7 T-47d and Mda-mb-231 Cell Growthmentioning

confidence: 75%

“…Because ATRA and most retinoids control cell proliferation via apoptosis among several other mechanisms in a variety of cancers Toma et al, 1997;Kotake-Nara et al, 2002;Afonja et al, 2004;Simeone and Tari, 2004) and also because of the cell cycle analysis data that suggests accumulation of cell in the sub-G phase, the apoptotic potential of our RAMBAs was evaluated. Retinoic acid metabolism blocking agents-induced apoptosis in MCF-7 and T47D cells was examined in three independent experiments with ATRA and 4-HPR as positive controls.…”

Section: Apoptosis Induced By Rambasmentioning

confidence: 99%

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

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Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER þ ve, MCF-7 and T-47D) and oestrogen receptor negative (ER Àve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumuor xenografts. The ER þ ve cell lines were more sensitive (IC 50 values between 3.0 and 609 nM) to the RAMBAs than the ER Àve MDA-MB-231 cell line (IC 50 ¼ 5.6 -24.0 mM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-a (ER-a). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (480%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, Po0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (Po0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer.

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“…The main mechanism by which ATRA inhibits the proliferation of breast cancer cells is by inducing G1 cell cycle arrest (Wilcken et al, 1996;Toma et al, 1997Toma et al, , 1998Mangiarotti et al, 1998). Breast cancer cells became growth arrested when they were incubated with ATRA for 3 or more days.…”

Section: Discussionmentioning

confidence: 99%

Her2/neu induces all-transretinoic acid (ATRA) resistance in breast cancer cells

et al. 2002

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We observed that all-trans retinoic acid (ATRA) inhibited the growth of MCF-7 breast cancer cells, but not those transfected with HER2/NEU or its transactivating ligand HEREGULIN. This suggests that Her2/ neu causes breast cancer cells to be resistant to the growth inhibitory effects of ATRA. To confirm this observation, MDA-MB-453 and BT-474 cells, which have high levels of Her2/neu and are resistant to ATRA, were incubated with the trastuzumab (Herceptin TM ) antibody so that we could determine whether inhibition of the expression and function of Her2/neu would resensitize these cells to ATRA. Indeed, we found that MDA-MB-453 and BT-474 cells treated with trastuzumab were growth inhibitory by ATRA. We then determined whether Her2/neu uses Grb2 and Akt proteins to induce ATRA resistance. Liposome-incorporated Grb2 antisense oligonucleotides (L-Grb2) and a dominant negative (DN) AKT mutant were used to down-regulate Grb2 expression and inhibit Akt activity, respectively. When incubated with L-Grb2 or transfected with the DN AKT mutant, ATRA-resistant, Her2/neuoverexpressing cells became sensitive to ATRA. Our results indicate that Her2/neu utilizes Grb2 and Akt proteins to induce ATRA resistance in breast cancer cells. ATRA sensitivity was also correlated with RARa protein levels since higher RARa protein levels were observed in cells in which the Her2/neu pathway was inhibited.

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Effects of ALL-trans-retinoic acid and 13-cis-retinoic acid on breast-cancer cell lines: Growth inhibition and apoptosis induction

Abstract: Interest has been increasingly focused on all-trans-retinoic acid (tRA) and 13-cis-retinoic acid (13cRA) in cancer chemoprevention and treatment. We have examined the in vitro effects of these 2 retinoic acids (

Cited by 114 publications

References 15 publications

All-trans retinoic acid (ATRA)-induced apoptosis is preceded by G1 arrest in human MCF-7 breast cancer cells

All-trans retinoic acid (ATRA)-induced apoptosis is preceded by G1 arrest in human MCF-7 breast cancer cells

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Her2/neu induces all-transretinoic acid (ATRA) resistance in breast cancer cells

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