Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells

Zhang, Manchao; Liu, Hongpeng; Guo, Ribo; Ling, Yan; Wu, Xiaojin; Li, Bihua; Roller, Peter P.; Wang, Shaomeng; Yang, Dajun

doi:10.1016/s0006-2952(03)00248-x

Cited by 157 publications

(143 citation statements)

References 61 publications

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“…With electron microscopy and the TUNEL assay, we confirmed that gossypol induces apoptosis in a concentrationdependent manner in both cell types. The apoptotic characteristics induced by gossypol were similar to those previously reported in spermatocytes and cancer cells [23,24] . To explore the mechanism of apoptosis induction by gossypol, we investigated the expression of Bcl-2 in both cell types.…”

Section: Discussionsupporting

confidence: 86%

Involvement of Bcl-2, Src, and ERα in gossypol-mediated growth inhibition and apoptosis in human uterine leiomyoma and myometrial cells

et al. 2010

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Aim:To investigate the effect of gossypol on the growth of cultured human uterine leiomyoma and myometrial cells, the level of Bcl-2 and the activity of Src and estrogen receptor (ERα). Methods: Human uterine leiomyoma and adjacent normal myometrial cells were cultured in vitro. Both cell types were treated with a graded concentration of gossypol. Cell viability was assayed using CCK-8. Morphological change was observed with optical and electronic microscopy. Apoptosis was evaluated using TUNEL assay. Levels of Bcl-2, ERα and Src were analyzed using Western blotting. Results: Gossypol significantly inhibited growth and promoted apoptosis in cultured human uterine leiomyoma cells with the IC 50 value and its corresponding 95% confidence intervals (CI) of 6.5 (4.0-10.5), 9.0 (4.9-16.5), and 7.5 (4.0-14.1) μmol/L at 20, 40, and 60 h, respectively. Gossypol exerted inhibitory effects on the myometrial cells with the IC 50 value and its 95% CI of 49.1 (28.3-85.0), 14.5 (7.7-27.4), and 2.6 (1.2-5.6) μmol/L at 20, 40, and 60 h, respectively. Compared with control, gossypol 0.1-3.0 μmol/L markedly decreased the protein expression of Bcl-2 (P<0.05) in both leiomyoma and myometrial cells in a concentration-dependent manner, and significantly suppressed the level of phospho-Tyr416Src (P<0.05) in both cell types at 3.0 µmol/L without obvious alteration of c-Src and phospho-Tyr527Src levels (P>0.05). In addition, gossypol markedly reduced both the expression of ERα (P<0.05) at the low concentration of 0.1 µmol/L in the myometrial cells and the level of phospho-ser167ERα (P<0.05) at the high concentration of 3.0 µmol/L in the leiomyoma cells. Conclusion: Gossypol inhibits proliferation and induces apoptosis in human uterine leiomyoma and myometrial cells. It is likely that the mechanisms of action involve reducing the protein level of Bcl-2 and the activity of Src and ERα.

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Section: Discussionsupporting

confidence: 86%

Involvement of Bcl-2, Src, and ERα in gossypol-mediated growth inhibition and apoptosis in human uterine leiomyoma and myometrial cells

et al. 2010

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“…Prostate cancer (PCa) is the most frequently diagnosed male malignancy and the second leading cause of male cancer death in most industrialized countries [1]. Recently, Asian countries, such as Japan and China, have also reported high incidences of PCa and consequent mortality rates.…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Zhang¹,

Huang²,

Mu³

et al. 2010

Asian J Androl

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We investigated the antiproliferative activity of (-)-gossypol on the human prostate cancer cell line PC3 in vitro and in vivo to elucidate its potential molecular mechanisms. Cell growth and viability were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell apoptosis was detected by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and electron microscopy. Expression of proliferating cell nuclear antigen (PCNA), Bcl-2, CD31, caspase-3 and caspase-8 in tumour tissue was determined by immunohistochemistry. The drug concentration that yielded 50% cell inhibition (IC50 value) was 4.74 mg mL -1 . In the PC-3 tumour xenograft study, (-)-gossypol (> 5 mg kg -1 ) given once a day for 7 days significantly inhibited tumour growth in a dose-dependent manner. Immunohistochemical analysis revealed that (-)-gossypol enhanced caspase-3 and caspase-8 expression and decreased the expression of PCNA, Bcl-2 and CD31 in tumour tissues. It suggested that cell apoptosis and inhibition of angiogenesis might contribute to the anticancer action of (-)-gossypol.

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“…There are also many reports claiming that gossypol can function as a BH3 mimetic. Specifically, gossypol is reported to inhibit BCL2 and BCLXL (20,21). Gossypol has demonstrated anti-tumor efficacy in a variety of systems, including cancer cell lines, mouse xenograft models, and ongoing clinical trials (22,23).…”

mentioning

confidence: 99%

Gossypol Increases Expression of the Pro-apoptotic BH3-only Protein NOXA through a Novel Mechanism Involving Phospholipase A2, Cytoplasmic Calcium, and Endoplasmic Reticulum Stress

Soderquist¹,

Danilov

Eastman

2014

Journal of Biological Chemistry

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Background:The mechanism through which gossypol mediates anti-cancer activity is poorly understood. Results: Gossypol rapidly activates phospholipase A2, increases cytoplasmic calcium, endoplasmic reticulum stress, and NOXA, and sensitizes cells to apoptosis. Conclusion: Phospholipase A2 is a novel target of gossypol. Significance: This pathway can explain many reported activities of gossypol including sensitization to the BCL2 inhibitor,

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Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells

Cited by 157 publications

References 61 publications

Involvement of Bcl-2, Src, and ERα in gossypol-mediated growth inhibition and apoptosis in human uterine leiomyoma and myometrial cells

Involvement of Bcl-2, Src, and ERα in gossypol-mediated growth inhibition and apoptosis in human uterine leiomyoma and myometrial cells

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

Gossypol Increases Expression of the Pro-apoptotic BH3-only Protein NOXA through a Novel Mechanism Involving Phospholipase A2, Cytoplasmic Calcium, and Endoplasmic Reticulum Stress

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