Reversal of cisplatin resistance with a BH3 mimetic, (−)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL

Bauer, Joshua A.; Trask, Douglas K.; Kumar, Bhavna; Los, Gerrit; Castro, J. Gonzalez; Lee, Julia Shin Jung; Chen, Jianyong; Wang, Shaomeng; Bradford, Carol R.; Carey, Thomas E.

doi:10.1158/1535-7163.mct-05-0081

Cited by 113 publications

(113 citation statements)

References 44 publications

(26 reference statements)

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“…The inhibitory effect of p65 siRNA on p21, IAP1, and BCL-XL are consistent with several recent studies, which indicate that these genes can act as inhibitors of apoptosis (36, 41 -45). IAP1 and BCL-XL have been shown to inhibit caspase and mitochondrial-mediated cell death (41,42), and BCL-XL overexpression or knockdown has been shown to modulate resistance of HNSCC to apoptosis (38). Evidence indicates that p21 may attenuate HDI-mediated apoptosis due to the ability of cytoplasmic p21 to bind to and inactivate procaspase-3 (43,44).…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Duan

Friedman

Nottingham

et al. 2007

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDI) can inhibit proliferation and enhance apoptosis in a wide range of malignancies. However, HDIs show relatively modest activity in head and neck squamous cell carcinomas (HNSCC), in which we have shown the activation of nuclear factor-KB (NF-KB; NF-KB1/RelA or p50/p65), a transcription factor that promotes expression of proliferative and antiapoptotic genes. In this study, we examined if HDIs enhance activation of NF-KB and target genes and if genetic or pharmacologic inhibition of NF-KB can sensitize HNSCC to HDIs. Limited activity of classic HDIs trichostatin A and sodium butyrate was associated with enhanced activation of NF-KB reporter activity in a panel of six HNSCC cell lines. HDIs enhanced NF-KB p50/p65 DNA binding and acetylation of the RelA p65 subunit. Transfection of small interfering RNAs targeting p65 strongly inhibited NF-KB expression and activation, induced cell cycle arrest and cell death, and further sensitized HNSCC cells when combined with HDIs. The p65 small interfering RNA inhibited HDI-enhanced expression of several NF-KB -inducible genes implicated in oncogenesis of HNSCC, such as p21, cyclin D1, and BCL-XL. Bortezomib, an inhibitor of proteasome-dependent NF-KB activation, also increased sensitization to trichostatin A, sodium butyrate, and a novel HDI, PXD101, in vitro, and to the antitumor effects of PXD101 in bortezomib-resistant UMSCC-11A xenografts. However, gastrointestinal toxicity, weight loss, and mortality of the combination were dose limiting and required parenteral fluid administration. We conclude that HDI-enhanced NF-KB activation is one of the major mechanisms of resistance of HNSCC to HDIs.

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Section: Discussionmentioning

confidence: 99%

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Duan

Friedman

Nottingham

et al. 2007

Molecular Cancer Therapeutics

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“…Cells were grown in HEPES-buffered RPMI 1640 supplemented with 5% FCS, 2 mmol/L glutamine, 0.01% sodium pyruvate, 5 Â 10 -5 mol/L 2-mercaptoethanol, and antibiotics (culture medium) at 37jC in a humidified atmosphere with 5% CO 2 . After the conventional trypsinization procedure, the cells were seeded at 1 Â 10 4 per well in 96-well plate, 2 Â 10 5 per well in 6-well plate, or 3 Â 10 4 per well in 4-well chamber slide, cultivated overnight, and then (17).…”

Section: Methodsmentioning

confidence: 99%

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić

Mijatović

Harhaji

et al. 2008

Molecular Cancer Therapeutics

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Preclinical studies have shown that nitric oxide (NO) -donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NOdeprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatinresistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.

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“…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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Reversal of cisplatin resistance with a BH3 mimetic, (−)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL

Cited by 113 publications

References 44 publications

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

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

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