A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells

Eck, K. M.; Yuan, Lin; Duffy, Lawrence K.; Ram, Prahlad T.; Ayettey, S.; Chen, I.; Cohn, Clarence; Reed, John C.; Hill, Steven M.

doi:10.1038/bjc.1998.357

Cited by 73 publications

(58 citation statements)

References 26 publications

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“…The study of Eck et al [33] showing that MLT given together with retinoic acid induced apoptosis in MCF-7 mammary cancer cells is compatible with our findings. Our results also corroborate the observation of Anisimow et al [34] who found that MLT inhibited cell proliferation and enhanced the number of apoptotic cells in 1,2-dimethylhydrazine-induced intestinal tumors.…”

Section: Discussionsupporting

confidence: 82%

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Winczyk¹,

Pawlikowski²,

Guerrero³

et al. 2002

Tumor Biol

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Experimental evidence has shown that melatonin (MLT) may act through both membrane and nuclear receptors. Moreover, it was proposed that the nuclear MLT receptor is identical with nuclear orphan receptors called RZR/ROR. Our earlier results suggest that the antitumor action of MLT depends mainly on nuclear signaling. In the present study, we investigated whether CGP 55644 (an antagonist of the nuclear RZR/RORα receptor) changes the oncostatic effects of MLT on murine Colon 38 cancer. The experiment was performed on adult male B6D2F1 mice. MLT or CGP were given either alone or combined during 10 days, and cell proliferation, apoptosis and the proliferation/apoptosis (P/A) ratio were determined. Cell proliferation was assessed by incorporation of bromodeoxyuridine into tumor cell nuclei (labeling index – LI). The number of apoptotic cells using the TUNEL method was considered as an index of apoptosis. It was found that MLT inhibited cell proliferation. Addition of CGP to MLT diminished the antiproliferative effect of MLT. Moreover, MLT increased the apoptotic index, but CGP decreased apoptosis. In addition, CGP given together with MLT blocked its proapoptotic effect. Given alone, MLT strongly lowered the P/A ratio, and addition of CGP to MLT abolished the effect of MLT on the P/A ratio. Based on our data, we conclude that nuclear RZR/RORα receptors participate in the oncostatic action of MLT.

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Section: Discussionsupporting

confidence: 82%

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Winczyk¹,

Pawlikowski²,

Guerrero³

et al. 2002

Tumor Biol

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“…The ability of retinoids to countermand cell survival, possibly by lowering Bcl-2 levels, is evident from the observation that cotreatment with RA and a conventional chemotherapeutic agent results in increased cytotoxicity over the drug alone (Wang et al, 2000). Similarly, Eck et al (1998) showed that sequential treatment with melatonin and all-trans RA induces apoptosis in both MCF-7 and T47D cells, although the response to either agent alone was simple growth inhibition. These workers also reported a decreased level of Bcl-2 and an increase in Bax following RA and melatonin, although we have not detected changes in Bax expression in either vectortransfected or cyclin D1-transfected MCF-7 and ZR-75 cells treated with RA.…”

Section: Discussionmentioning

confidence: 96%

Ectopic expression of cyclin D1 amplifies a retinoic acid-induced mitochondrial death pathway in breast cancer cells

et al. 2001

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All-trans retinoic acid inhibits growth associated with downregulation of cyclin D1 and can cause low level apoptosis in estrogen receptor positive breast cancer cell lines. The cyclin D1 gene is ampli®ed and/or the protein overexpressed in about one-third of breast cancers. Constitutive expression of cyclin D1 in estrogen receptor positive MCF-7 and ZR-75 breast cancer cells (MCF-7(cycD1) and ZR-75(cycD1)) Increased the fraction of cells in S phase and reduced the G1 accumulation following retinoic acid treatment compared with control cells. However, culture of MCF-7(cycD1) with 1 mM alltrans retinoic acid resulted in about threefold greater growth inhibition compared with vector-transfected cells. Hoechst staining of DNA and in situ DNA end-labeling analysis indicated that MCF-7(cycD1) and ZR-75(cycD1) cultures contained 4 ± 6-fold more retinoic acid-induced apoptotic nuclei as vector-transfected cells. Retinoic acid treatment of vector-transfected clones resulted in Bax protein activation as assessed by exposure of the NH 2 -terminus of Bax but the proportion of cells containing activated Bax was increased in cyclin D-expressing cells treated with retinoic acid. The latter cells also displayed both immunocytochemical and biochemical evidence of translocation of cytochrome c into the cytosol following RA-treatment. Retinoic acid markedly decreased the Bcl-2 levels in MCF-7 and ZR-75 cells. Accordingly, coexpression of Bcl-2 and cyclin D1 rendered the cells resistant to retinoic acid-induced apoptosis. We conclude that constitutive expression of cyclin D1 sensitizes ER-positive breast cancer cells to a retinoic acid-induced mitochondrial death pathway involving Bax activation, cytochrome c release and caspase-9 cleavage. Oncogene (2001) 20, 3506 ± 3518.

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“…In fact, apoptosis induced by tamoxifen (16,32), toremifene (33), and estrogen ablation (34) in MCF-7 is associated with induction of TGF-␤ expression. Furthermore, treatment of MCF-7 cells with melatonin followed by all trans retinoic acids (35), and the tyrosine kinase inhibitor genistein (36) also induced apoptosis accompanied by increased TGF-␤ expression. As mentioned above, CTGF gene expression is regulated by TGF-␤ (37), and in vascular smooth muscle cells CTGF mRNA increased 20-fold over basal level after stimulation with TGF-␤.…”

Section: Discussionmentioning

confidence: 99%

“…Bcl2 protein is considered a major factor in the inhibition of apoptosis in many human cancers (38 -40), and Bcl2 also regulates apoptosis in MCF-7. For example, apoptosis induced by melatonin followed by all trans-retinoic acids (35), , lonidamine (42), and basic fibroblast growth factor (43) in MCF-7 is associated with downregulation of Bcl2. Moreover treatment with melatonin followed by all trans-retinoic acids (35) or Ro 41-5253 (41) also increases TGF-␤ expression in MCF-7.…”

Section: Discussionmentioning

confidence: 99%

“…For example, apoptosis induced by melatonin followed by all trans-retinoic acids (35), , lonidamine (42), and basic fibroblast growth factor (43) in MCF-7 is associated with downregulation of Bcl2. Moreover treatment with melatonin followed by all trans-retinoic acids (35) or Ro 41-5253 (41) also increases TGF-␤ expression in MCF-7. Bax is a dominant negative inhibitor of Bcl2, and overexpression of Bax sensitizes MCF-7 to radiation-induced apoptosis (44).…”

Section: Discussionmentioning

confidence: 99%

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Connective Tissue Growth Factor Induces Apoptosis in Human Breast Cancer Cell Line MCF-7

Hishikawa¹,

Oemar²,

Tanner³

et al. 1999

Journal of Biological Chemistry

150

105

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Connective tissue growth factor (CTGF) is a member of an emerging CCN gene family that is implicated in various diseases associated with fibro-proliferative disorder including scleroderma and atherosclerosis. The function of CTGF in human cancer is largely unknown. We now show that CTGF induces apoptosis in the human breast cancer cell line MCF-7. CTGF mRNA was completely absent in MCF-7 but strongly induced by treatment with transforming growth factor ␤ (TGF-␤). TGF-␤ by itself induced apoptosis in MCF-7, and this effect was reversed by co-treatment with CTGF antisense oligonucleotide. Overexpression of CTGF gene in transiently transfected MCF-7 cells significantly augmented apoptosis. Moreover, recombinant CTGF protein significantly enhanced apoptosis in MCF-7 cells as evaluated by DNA fragmentation, Tdt-mediated dUTP biotin nick end-labeling staining, flow cytometry analysis, and nuclear staining using Hoechst 33258. Finally, recombinant CTGF showed no effect on Bax protein expression but significantly reduced Bcl2 protein expression. Taken together, these results suggest that CTGF is a major inducer of apoptosis in the human breast cancer cell line MCF-7 and that TGF-␤-induced apoptosis in MCF-7 cells is mediated, in part, by CTGF. Connective tissue growth factor (CTGF)1 is a member of an emerging gene family known as the CCN family (1), which includes CTGF (also known as fisp-12), CYR61(cysteine-rich 61/CEF10), Nov (nephroblastoma overexpressed) and the newly discovered WISP1/elm1, WISP2/rCop1, and WISP3 (2-5). CTGF was originally identified in conditioned medium of human umbilical vein endothelial cells (6) and plays a role in various human diseases including systemic scleroderma (7), atherosclerosis (8), renal diseases (9), hepatic fibrosis in biliary atresia (10), and malignant melanoma (11). A common finding in most of these diseases was a high level expression of CTGF in fibro-proliferative areas of affected tissues. In most cases, a direct correlation between high level CTGF expression and high levels of transforming growth factor-␤ (TGF-␤) expression could be established. In fact, CTGF gene expression has been shown to be regulated by TGF-␤ (2).TGF-␤ is a pleiotropic growth modulator with a wide variety of activities on different cell types. TGF-␤ stimulates proliferation of mesenchymal cells but inhibits that of endothelial (12) and epithelial cells (13). TGF-␤ is also known to inhibit the proliferation of a variety of cancer cell lines including the human breast cancer cell line 15). In fact, the anticancer effect of tamoxifen has been attributed to indirect activation of TGF-␤ pathway and induction of apoptosis by TGF-␤ (16). Because CTGF is thought to be a mediator of TGF-␤ action, it is conceivable that CTGF may also inhibit cancer cell proliferation by inducing apoptosis in these cells. In the present study, we utilized antisense technology, transient overexpression techniques, and recombinant CTGF protein to gain insight into the biological function of CTGF in the MCF-7 breast cancer cell line...

show abstract

A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells

Cited by 73 publications

References 26 publications

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Ectopic expression of cyclin D1 amplifies a retinoic acid-induced mitochondrial death pathway in breast cancer cells

Connective Tissue Growth Factor Induces Apoptosis in Human Breast Cancer Cell Line MCF-7

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