Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway

Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in A/J mice. We also studied the effect of kava to liver. At a dose of 10 mg/g diet, 30-week kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of kava against lung tumorigenesis. Mechanistically, kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor κBNF-κB, a potential upstream mechanism of kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of kava.

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“…The effect of kava on NF-κB in lung tumors was evaluated by immunoblotting of p65, the active form of NF-κB (53). As shown in Fig.…”

Section: Kava Inhibits Nf-κb Activation In Response To Carcinogenmentioning

confidence: 99%

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Johnson

Kassie

O’Sullivan

et al. 2008

Cancer Prevention Research

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“…Both of the tested drugs induced cell cycle arrest at G2/M phase (Pozarowski et al, 2004;Mansilla et al, 2006;Lee et al, 2007;Pellicciotta et al, 2013). It should be highlighted that in the cited studies, bisanthracycline was used at much higher concentrations than in our experiments, which explains the lack of the influence of 10 nM WP 631 on cell cycle distribution at all tested times in our experiments.…”

Section: Discussionmentioning

confidence: 48%

Why a Combination of WP 631 and Epo B is an Improvement on the Drugs Singly - Involvement in the Cell Cycle and Mitotic Slippage

Bukowska

Rogalska²,

Forma³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Our previous studies clearly demonstrated that a combination of WP 631 and Epo B has higher activity against ovarian cancer cells than either of these compounds used separately. In order to fully understand the exact mechanism of action in combination, we assessed effects on the cell cycle of SKOV-3 cells. We evaluated three control points essential for WP 631 and Epo B action to determine which cell cycle-regulating proteins (CDK1/cyclin B complex, EpCAM or HMGB1) mediate activity. The effects of the drug on the cell cycle were measured based on the nuclear DNA content using flow cytometry. Expression of cell cycle-regulating genes was analyzed using real-time PCR. It was discovered that WP 631, at the tested concentration, did not affect the SKOV-3 cell cycle. Epo B caused significant G2/M arrest, whereas the drug combination induced stronger apoptosis and lower mitotic arrest than Epo B alone. This is very important information from the point of view of the fight against cancer, as, while mitotic arrest in Epo B-treated cells could be overcame after DNA damage repair, apoptosis which occurs after mitotic slippage in combination-treated cells is irreversible. It clearly explains the higher activity of the drug combination in comparison to Epo B alone. Epo B acts via the CDK1/cyclin B complex and has the ability to inhibit CDK1, which may be a promising strategy for ovarian cancer treatment in the future. The drug combination diminishes EpCAM and HMGB1 expression to a greater degree than either WP 631 and Epo B alone. Owing to the fact that the high expression of these two proteins is a poor prognostic factor for ovarian cancer, a decrease in their expression, observed in our studies, may result in improved efficacy of cancer therapy. The presented findings show that the combination of WP 631 and Epo B is a better therapeutic option than either of these drugs alone.

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“…Since a smaller BMI gain increased the risk of endometrial cancer in Asian women, an increase in adiposity may contribute to the development of endometrial cancer in normal-weight or underweight women. Another possible explanation might be the effects of nonestrogenic factors, such as race differences in epigenetic factors [22], polymorphism in hormonal receptors [23], or alternative oncological mediators, including aneuploidy and mutations in PTEN, K-ras and p53 [24]. …”

Section: Discussionmentioning

confidence: 99%

Uterine Endometrial Carcinoma: 10 Years’ Experience with Long-Term Follow-Up at a Single Korean Institution

Lee

Kim²,

Choi³

et al. 2012

Gynecol Obstet Invest

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Aim: To evaluate prognostic factors in Korean patients with endometrial cancer. Methods: A retrospective analysis was conducted on 248 patients who were staged surgically at the Samsung Medical Center between 1995 and 2004. Survival data were analyzed using Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression method. Results: The median age was 51 years (range 21–75), which was younger than in previous studies in Western patients, and the age of 50 years was the cutoff to predict survival. More than half (55.6%) were normal weight or underweight (BMI <25). Multivariate analysis revealed that age, Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage, and histopathology were independent predictors of disease-free survival, and FIGO stage and p53 mutation were independent prognostic factors for disease-specific survival (DSS). The 5-year DSS for patients with stage I, II, III and IV disease was 95.6, 93.8, 69.8 and 50%, respectively. The 5-year DSS rate for patients with a p53 mutation was 84.4%, compared with 97.1% for patients without. Conclusions: Korean patients with endometrial cancer were younger and had a lower BMI than previously reported. Furthermore, age greater than 50 years was predictive of a poor outcome. Age, FIGO stage, histopathology and a p53 mutation were independent prognostic factors for survival.

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Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-κB/IκB kinase signal pathway

Cited by 33 publications

References 34 publications

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Chemopreventive Effect of Kava on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone plus Benzo[a]pyrene–Induced Lung Tumorigenesis in A/J Mice

Why a Combination of WP 631 and Epo B is an Improvement on the Drugs Singly - Involvement in the Cell Cycle and Mitotic Slippage

Uterine Endometrial Carcinoma: 10 Years’ Experience with Long-Term Follow-Up at a Single Korean Institution

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