Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN

Chu, Tian‐Huei; Chan, Hoi‐Hung; Kuo, Hsi-Kung; Liu, Lifen; Hu, Tsung–Hui; Sun, Cheuk‐Kwan; Kung, Mei-Lang; Lin, Shih Pin; Wang, E-Ming; Ma, Yi-Ling; Cheng, Kwan-Hung; Lai, Kwok Hung; Wen, Zhi‐Hong; Hsu, Ping‐I; Tai, Ming‐Hong

doi:10.18632/oncotarget.1745

Cited by 51 publications

(50 citation statements)

References 51 publications

(65 reference statements)

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“…Finally, celecoxib administration did not worsen epirubicin-induced myelotoxicity. Given that celecoxib therapy is safe and well tolerated for HCCbearing animals [17], the present study supports the potential of combined epirubicin and celecoxib therapy for advanced or unresectable HCC.…”

Section: Discussionsupporting

confidence: 74%

“…Our previous study showed that epirubicin treatment effectively delayed the tumor growth in orthotropic hepatoma model . Moreover, we have also found that celecoxib therapy potently suppressed HCC progression and extended the survival rate of HCC‐bearing rats through depletion of CD44/CD133 hepatic CSCs . But epirubicin or celecoxib monotherapy did not eradicate hepatic tumor and reduce tumor size of established hepatoma in our previous researches.…”

Section: Introductionmentioning

confidence: 82%

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Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Chu

Chan

et al. 2018

Cancer Medicine

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Epirubicin is a chemotherapy agent for hepatocellular carcinoma (HCC). However, the outcome of HCC patients receiving epirubicin remains unsatisfactory. Moreover, our previous study indicated that celecoxib suppresses HCC progression and liver cancer stemness. This study evaluated the potential of celecoxib to serve as a complementary therapy during epirubicin treatment. Cell proliferation, apoptosis, invasiveness, and anchorage‐independent growth were analyzed in hepatoma cells. Therapeutic efficacy was validated in rat orthotopic Novikoff hepatoma. After animal sacrifice, the antitumor mechanism of celecoxib and epirubicin combined therapy was investigated by histological analysis. Celecoxib enhanced the cytotoxic activity of epirubicin in HCC cells by promoting apoptosis. Besides, celecoxib potentiated the antineoplastic function of epirubicin in inhibiting the invasiveness and anchorage‐independent growth of HCC cells. Ultrasound monitoring showed that combined therapy was more potent than either therapy alone in perturbing HCC progression. Consistently, the size and weight of dissected HCC tissues from rats receiving combined therapy were smallest among all groups. HCC treated with combined therapy exhibited the highest prevalence of apoptotic cells, which was accompanied by reduced proliferating and angiogenic activities in tumor tissues. Moreover, the expression levels of cancer stemness markers (CD44 and CD133) and drug transporter MDR‐1 were significantly diminished in rats receiving combined therapy. Besides, celecoxib treatment increased the infiltration of cytotoxic T lymphocytes (CTLs) and reduced the number of regulatory T cells (Tregs), tumor‐associated macrophages (TAMs), and the expression of immune checkpoint PD‐L1 in HCC tissues during epirubicin therapy. Celecoxib augmented the therapeutic efficacy while modulated cancer stemness and antitumor immunity. Thus, celecoxib may serve as complementary therapy to improve the outcome of patients with advanced HCC during epirubicin treatment.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 82%

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Chu

Chan

et al. 2018

Cancer Medicine

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“…Nevertheless, the association is quite remarkable. Given the newly available and effective therapies for hepatitis B and C (and possibly also anti-inflammatory agent, such as aspirin, NSAIDS, Cox inhibitors, in patients without bleeding disorder), it may be that their use in suppressing hepatic inflammation and/or improving liver function in HCC patients with inflamed livers, offer the possibility of decreasing HCC aggressiveness through improvement of the underlying liver function [28][29][30][31][32]. What might be the mechanisms by which liver function parameters could influence HCC aggressiveness Two possible general explanations might be considered.…”

Section: Discussionmentioning

confidence: 99%

An HCC Aggressiveness Index and Blood GTP, Bilirubin and Platelet Levels

Carr¹,

Guerra²

2016

J Integr Oncol

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Four HCC characteristics typically inform tumor behavior: maximum tumor size, number of nodules, portal vein thrombosis and serum AFP level. The sum of these parameters was recently published as an HCC Aggressiveness Index. We aimed to validate this index retrospectively in a larger and independent HCC cohort of 2706 Italian HCC patients, and to evaluate a possible relationship between the index and liver function parameters. The scores in the HCC Aggressiveness Index were again found to significantly relate to patient survival. Furthermore, in a multiple logistic regression model of the Aggressiveness Index score categories, there were significant differences in several liver parameter terciles amongst the score categories, suggesting a relationship of liver function to tumor aggressiveness. It was concluded that a prognostically significant Tumor Aggressiveness Index was validated and was found to be related to levels of some common liver function parameters.

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“…Besides, COX-2 is widely expressed and profoundly linked to poor prognosis in a variety of malignant tumors [12, 13]. What's more, inhibition of COX-2 has a reversed effect on cancer progression [14–18]. Therefore, COX-2 might be a potential prognostic factor to predict the survival in patients with cancers.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis

et al. 2016

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Several studies have assessed the clinicopathological and prognostic value of cyclooxygenase-2 (COX-2) expression in patients with head and neck cancer (HNC), but their results remain controversial. To address this issue, a meta-analysis was carried out. A total of 29 studies involving 2430 patients were subjected to final analysis. Our results indicated that COX-2 expression was not statistically associated with advanced tumor stage (OR, 1.23; 95% CI, 0.98–1.55) but correlated with high risk of lymph node metastasis (OR, 1.28; 95% CI, 1.03–1.60) and advanced TNM stage (OR, 1.33; 95% CI, 1.06–1.66). Moreover, COX-2 expression had significant effect on poor OS (HR, 1.93; 95% CI, 1.29–2.90), RFS (HR, 2.02; 95% CI, 1.00–4.08) and DFS (HR, 5.14; 95% CI, 2.84–9.31). The results of subgroup analyses revealed that COX-2 expression was related with high possibility of lymph node metastasis in oral cancer (OR, 1.49; 95% CI, 1.01–2.20) and advanced TNM stage in oral cancer (OR, 1.58; 95% CI, 1.05–2.37) and no site-specific HNC (OR, 1.64; 95% CI, 1.02–2.62). However, subgroup analyses only showed a tendency without statistically significant association between COX-2 expression and survival. Significant heterogeneity was not found when analyzing clinicopathological data, but it appeared when considering survival data. No publication bias was detected in this study. This meta-analysis suggested that COX-2 expression could act as a prognostic factor for patients with HNC.

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Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN

Cited by 51 publications

References 51 publications

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

An HCC Aggressiveness Index and Blood GTP, Bilirubin and Platelet Levels

Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis

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