Gossypol inhibition of mitosis, cyclin D1 and Rb protein in human mammary cancer cells and cyclin-D1 transfected human fibrosarcoma cells

Abstract

Summary The antiproliferative effects of gossypol on human MCF-7 mammary cancer cells and cyclin Dl-transfected HT-1060 human fibrosarcoma cells were investigated by cell cycle analysis and effects on the cell cycle regulatory proteins Rb and cyclin Dl. Flow cytometry of MCF-7 cells at 24 h indicated that 10 gm gossypol inhibited DNA synthesis by producing a G,/S block. Western blot analysis using antihuman Rb antibodies and anti-human cyclin Dl antibodies in MCF-7 cells and high-and low-expression cyclin Dl-transfected fibrosarcoma cells indicated that, after 6 h exposure, gossypol decreased the expression levels of these proteins in a dose-dependent manner. Gossypol also decreased the ratio of phosphorylated to unphosphorylated Rb protein in human mammary cancer and fibrosarcoma cell lines. Gossypol (10 gM) treated also decreased cyclin D1-associated kinase activity on histone Hi used as a substrate in MCF-7 cells. These results suggest that gossypol might suppress growth by modulating the expression of cell cycle regulatory proteins Rb and cyclin Dl and the phosphorylation of Rb protein.

Inhibition of proliferation of prostate cancer cell line, PC-3, in vitro and in vivo using (−)-gossypol

“…Tumour volumes were measured every 3 days using a calliper and calculated according to the formula (L × W 2 )/2, where L and W are length and width, respectively [14]. When the tumours reached an appropriate size (200-250 mm 3 ), the mice were randomized into four groups of 10 mice and then treated with either (-)-gossypol (2.5, 5.0 or 10.0 mg kg -1 i.p. q.d) or DMSO (vehicle) for 7 days.…”

“…Recent studies have focused on 391 npg the proapoptotic activity of (-)-gossypol. Previously, research on gossypol in relation to cancer has focused mainly on the antiproliferative activity of (±)-gossypol in a variety of cancers in vitro and in vivo, including breast [3], bladder [4], pancreas [5], lung [6], colon [1] and prostate [7] and cancers of the head and neck [8,9]. These anticancer effects have been attributed to the (-)-enantiomer, which is a more potent inhibitor of cancer cell growth [10].…”

Tissue array for Tp53 , C-myc , CCND1 gene over-expression in different tumors

“…CCND1 forms a holoenzyme with a cyclin-dependent kinase (CDK), either CDK4 or CDK6 that phosphorylates the retinoblastoma gene product of pRb. Since the phosphorylation of pRb results in the release of E2F transcription factors, freeing them to stimulate transcription of growthpromoting target genes, over-expression of CCND1 promotes tumor progression through the G1 phase of cell cycle in cells grown on a substratum [5,6] . Overexpression of CCND1 has been reported in a variety of human tumors including cancers of the lung, head, neck, and bladder [7] .…”

Gossypol inhibits the growth of MAT-LyLu prostate cancer cells by modulation of TGFβ/Akt signaling

“…Ligueros et al demonstrated that GP arrested the cell cycle at G1/S phase by decreasing Rb expression, Rb phosphorylation, and cycle D1 protein expression in human MCF-7 breast cancer cells (8). Thus, we aimed to determine whether GP affects the expression of cell cycle-regulated proteins, such as Cdk4, cyclin D1, Rb and phospho-Rb in MAT-LyLu cells.…”

“…It is well documented that GP inhibits the proliferation of many human cancer cells in vitro and in vivo (5)(6)(7)(8)(9)(10). For example, GP significantly inhibited the growth of PC-3, DU-145, MCF-7 cells (6,(8)(9)(10) as well as the in vivo growth and metastasis of prostate cancer MAT-LyLu cells after implantation into Copenhagen rats (5). GP induces cell cycle arrest at G0/G1 phase in human prostate cancer PC-3 cells (6) or induces apoptosis in PC-3 (11) and colon cancer HT-29 cells (12).…”