A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system

Zennami, Kenji; Yoshikawa, Kazuhiro; Kondo, Eisaku; Nakamura, Kogenta; Upsilonamada, Y; Velasco, Marco A. De; Tanaka, Motoyoshi; Uemura, Hirotsugu; Shimazui, Toru; Akaza, Hideyuki; Saga, Shinsuke; Ueda, Ryuzo; Honda, Nobuaki

doi:10.3892/or.2011.1290

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…Meanwhile, through Phase I and II clinical trials, studies have revealed that CDK4/6 is an attractive target in p16 related pathway for anticancer therapy [ 49 – 51 ]. Furthermore, previous study also suggested that p16 functional peptide, as a molecular targeting agent, showed effective reactions for the treatment of renal cell carcinoma [ 52 ]. The results of these researches and our current meta-analysis had the effect of mutual authentication.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Clinicopathological Significance of Downregulated p16 Expression in Patients with Bladder Cancer: A Systematic Review and Meta-Analysis

Gan

Lin

et al. 2016

Disease Markers

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p16, encoded by the CDKN2A gene, is a tumor suppressor that has been widely studied in cancer research. However, the relationship of p16 with prognostic and clinicopathological parameters in patients with bladder cancer remains unclear. Data inclusion criteria were articles reporting on the relationship between p16 expression and the prognosis or clinicopathology in patients with bladder cancer. Meta-analyses were performed with Stata software. Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated to evaluate the relative risks. The source of heterogeneity was analyzed by subgroup analysis. A total of 37 studies with 2246 cases were included and analyzed. The results identified an important link between downregulated p16 expression and poor prognosis in patients with bladder cancer in terms of recurrence-free survival (RFS), overall survival (OS), progression-free survival (PFS), and some clinicopathological parameters including clinical staging, pathological degree, and lymph node metastasis. Subgroup analysis also showed that low p16 expression could function as a warning sign for RFS and PFS in patients with early-stage (Ta–T1) bladder cancer. In conclusion, p16 might play an essential role in the deterioration of bladder cancer and could serve as a biomarker for the prediction for patients' progression and prognosis.

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Section: Discussionmentioning

confidence: 99%

Prognostic and Clinicopathological Significance of Downregulated p16 Expression in Patients with Bladder Cancer: A Systematic Review and Meta-Analysis

Gan

Lin

et al. 2016

Disease Markers

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Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

Chen

Liú²,

Zhao³

et al. 2014

DNA and Cell Biology

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Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14-2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37-4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63-4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57-2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03-3.85, p=0.041; location: OR=2.49, 95% CI: 1.95-3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.

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Systemic transduction of p16INK4a antitumor peptide inhibits lung metastasis of the MBT‑2 bladder tumor cell line in mice

et al. 2018

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p16 INK4a (p16) is a key molecule in bladder tumor (BT) development. We previously reported that a p16 antitumor peptide inhibited the growth of subcutaneous BT grafts in mice through restoration of p16 function using a Wr-T peptide transporter system. In the present study, the efficacy of mouse p16 peptide administration in a mouse lung metastasis model for BT and also the toxicity of peptides by cardiac peptide injection were evaluated. Mouse lung metastases were developed by tail vein injection of a p16-deficient MBT-2 cell line. Six-week-old C3H/He female mice were divided into three groups: A control group (n=12) receiving no treatment; a group treated once on the 3rd experimental day (n=12); and a group treated three times on the 3rd, 5th and 7th experimental days (n=10) with an injection of a mixture of 80 nmol mouse p16 peptide and 50 nmol Wr-T into the tail vein. At the 14th experimental day, the lung metastases were histologically evaluated. Lung metastases were observed in 100% (12/12), 41.7% (5/12) and 30% (3/10) of the aforementioned three groups, respectively. The number and area of metastatic lung tumors were significantly different between control and treatment groups (control vs. triple treatment group for the number and area, P=0.0029 and P=0.0296, respectively). Immunohistochemistry demonstrated that phosphorylated retinoblastoma (Rb) protein was decreased in lung tumors of the treatment groups, compared with the control group. The toxicity of p16 peptide transduction was evaluated by using low-dose treatment (three dosages) and high-dose treatment (two dosages) on three male and three female C3H/He mice in early and late experimental phases. In low and high dose groups, no notable change was determined in body weight or blood analyses in early or late phases following mouse p16 peptide administration. In addition, no notable change was observed histologically in bone marrow of treatment groups. To conclude, systemic p16 peptide administration decreased lung tumor development in a mouse metastatic BT model without severe adverse events, as assessed by blood analyses and histological evaluation.

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A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system

Cited by 3 publications

References 17 publications

Prognostic and Clinicopathological Significance of Downregulated p16 Expression in Patients with Bladder Cancer: A Systematic Review and Meta-Analysis

Prognostic and Clinicopathological Significance of Downregulated p16 Expression in Patients with Bladder Cancer: A Systematic Review and Meta-Analysis

Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

Systemic transduction of p16INK4a antitumor peptide inhibits lung metastasis of the MBT‑2 bladder tumor cell line in mice

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