Anti-angiogenic therapy has been successfully applied to treat colorectal cancer (CRC). Ginsenoside Rg3, derived from the Chinese herb ginseng, has anti-vascularization effects and can inhibit tumor ...growth and metastasis, and can sensitize cancer cells to chemotherapy. Therefore, in the present study, we investigated whether Rg3 could be appropriate for CRC treatment. Growth of CRC cells was assessed by an MTT (methyl thiazolyl tetrazolium) assay in vitro and using orthotopic xenograft models in vivo. mRNA expression was evaluated using real-time PCR. Protein levels were tested by western blotting, flow cytometry and immunohistochemistry. Migration was determined using a wound-healing assay. Stemness was further confirmed using a plate clone formation assay. We found that Rg3 repressed the growth and stemness of CRC cells both in vitro and in vivo. Rg3 also impaired the migration of CRC cells in vitro. Rg3 downregulated the expressions of angiogenesis-related genes, and repressed the vascularization of CRC xenografts. In addition, Rg3 strengthened the cytotoxicity of 5-Fluorouracil and oxaliplatin against orthotopic xenografts in vivo. Moreover, Rg3 downregulated the expressions of B7-H1 and B7-H3, high expressions of which were associated with reduced overall survival (OS) of CRC patients. Hence, Rg3 not only repressed the growth and stemness of CRC cells, but could also remodel the tumor microenvironment through repressing angiogenesis and promoting antitumor immunity. Therefore, Rg3 could be a novel therapeutic for the CRC treatment.
Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is ...particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells.
Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay.
TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs
-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU.
TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Multiple cancers arise from sites of infection, chronic irritation, and inflammation. It has been widely accepted that pancreatic cancer is an inflammation-driven cancer. In this study, we ...investigated the application value of systemic inflammatory markers, neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in the prediction of chemotherapy response and prognosis in patients with late pancreatic cancer. 122 patients with inoperable pancreatic cancers were included and separated into two groups according to median values of NLR or PLR (NLR low:<3.81 or NLR high:≥3.81, and PLR low:<142.14 or PLR high≥142.14, respectively). Baseline NLR and PLR levels were significantly higher in pancreatic cancer patients compared with the healthy subjects. Neither of the baseline NLR or PLR levels could predict outcomes. Patients with low baseline level of NLR, but not PLR, had better responses to chemotherapy. Changes in NLR, but not PLR levels, were associated with the therapeutic efficacy. Patients who stayed in or dropped into the low NLR level subgroup after first-line chemotherapy had better responses, comparing to those stayed in or jumped into the high NLR level group. No similar results could be observed when the PLR level was investigated. Therefore, NLR is a more sensitive biomarker than PLR in the prediction of chemotherapy response of patients.
Background:
Lung cancer is the leading cause of cancer death. Platelet-related indictors, including platelet count, plateletcrit, mean platelet volume, and platelet distribution width, not only ...associate with morphology and functions of platelet but also correlate with tumor development and metastasis. In the present study, we investigated the values of platelet-related indictors in the prognosis evaluation of resectable lung cancers.
Methods:
In total, 101 patients with resectable lung cancer were recruited in this study. Patients were divided into 2 groups according to the median pretreatment values. To evaluate the individual value changes after treatment, we introduced the concept of post-/pretreatment ratio (≤1 indicated value was not increased after treatment, while >1 suggested increased value).
Results:
The high pretreatment platelet count level was correlated with larger tumor size. High pretreatment plateletcrit level was associated with more lymph nodes metastasis. Patients with high pretreatment plateletcrit level had worse overall survival, whereas pretreatment platelet count, mean platelet volume, and platelet distribution width levels were not correlated with outcomes. Surgery had no impact on the values of platelet count, plateletcrit, mean platelet volume, or platelet distribution width. Adjuvant chemotherapy significantly decreased the values of platelet count and plateletcrit, whereas it had no effect on the values of mean platelet volume or platelet distribution width. Whole course of treatment (surgery combined with adjuvant chemotherapy) significantly decreased the values of platelet count and platelet distribution width, whereas it had no effect on the values of plateletcrit or mean platelet volume. Post-/pretreatment platelet count, plateletcrit, mean platelet volume, and platelet distribution width ratios were not correlated with outcomes. Univariate analyses demonstrated that American Joint Committee on Cancer stage and pretreatment plateletcrit level were significant risk factors for prognosis. Cox regression analysis revealed that no factor independently associated with worse survival.
Conclusion:
Pretreatment plateletcrit level could be a potential prognostic factor in resectable lung cancers.
Colorectal cancer (CRC) represents the third most common malignancy worldwide. The aim of the present study was to investigate the predictive values of platelet-associated indicators, including ...platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV) and platelet distribution width (PDW) in patients with resectable CRC. The current retrospective study included 153 patients who were pathologically diagnosed with resectable CRC. The patients were divided into two groups according to the median value of PLT, PCT, MPV or PDW. To evaluate the changes in PLT, PCT, MPV and PDW following resection and adjuvant chemotherapy, the concept of post-/pre-treatment PLT, PCT, MPV and PDW ratios was introduced, where <1 indicated decreased PLT, PCT, MPV and PDW values after treatment, and where ≥1 suggested stable or increased values. It was revealed that a low MPV prior to treatment correlated with a higher tumor stage. Surgery significantly decreased MPV, but had no impact on PLT, PCT or PDW. Adjuvant chemotherapy significantly decreased PLT and PCT, increased MPV and had no effect on PDW. After the whole course of treatment (surgery combined with adjuvant chemotherapy), PLT, PCT and PDW were significantly decreased. Kaplan-Meier plots illustrated that patients with a post-/pre-treatment MPV ratio <1 had poorer overall survival (OS), whereas the post-/pre-treatment ratios for PLT, PCT and PDW did not correlate with patient outcome. Multivariate Cox regression analysis revealed that sex, tumor size and the post-/pre-treatment MPV ratio were prognostic factors for OS. Therefore, the present results may suggest MPV as a potential prognostic factor in resectable CRC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cantharidin, one of the active components of mylabris, is believed to have antitumor activity. Cantharidin selectively inhibits protein phosphatase 2A (PP2A), which can repress multiple oncogenic ...kinases (ERK, JNK, PKC, and NF-κB). Researches in vitro have shown that cantharidin suppresses cell viability and metastasis in pancreatic cancer cells. This study aims to investigate the effects of cantharidin on pancreatic cancer xenografts in vivo. Xenograft models were established using cells stably expressing luciferase. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated proangiogenic and downregulated antiangiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-α, and VEGF. Inhibitors of ERK, JNK, PKC, and NF-κB pathway attenuated the cantharidin-induced changes to proangiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar, antagonized the proangiogenic effect of cantharidin or its derivatives. These regimens presented remarkable additive antitumor effects in vivo. Although cantharidin presents antitumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable proangiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of antivascularization therapy.
Cantharidin is an inhibitor of protein phosphatase 2 A (PP2A), and has been frequently used in clinical practice. In our previous study, we proved that cantharidin could arrest cell cycle in G2/M ...phase. Since cells at G2/M phase are sensitive to radiotherapy, in the present study, we investigated the radiotherapy-sesitization effect of cantharidin and the potential mechanisms involved.
Cell growth was determined by MTT assay. Cell cycle was evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. Expression of mRNA was tested by microarray assay and real-time PCR. Clinical information and RNA-Seq expression data were derived from The Cancer Genome Atlas (TCGA) pancreatic cancer cohort. Survival analysis was obtained by Kaplan-Meier estimates.
Cantharidin strengthened the growth inhibition effect of irradiation. Cantharidin drove pancreatic cancer cells out of quiescent G0/G1 phase and arrested cell cycle in G2/M phase. As a result, cantharidin strengthened DNA damage which was induced by irradiation. Moreover, cantharidin repressed expressions of several genes participating in DNA damage repair, including UBE2T, RPA1, GTF2HH5, LIG1, POLD3, RMI2, XRCC1, PRKDC, FANC1, FAAP100, RAD50, RAD51D, RAD51B and DMC1, through JNK, ERK, PKC, p38 and/or NF-κB pathway dependent manners. Among these genes, worse overall survival for pancreatic cancer patients were associated with high mRNA expressions of POLD3, RMI2, PRKDC, FANC1, RAD50 and RAD51B, all of which could be down-regulated by cantharidin.
Cantharidin can sensitize pancreatic cancer cells to radiotherapy. Multiple mechanisms, including cell cycle regulation, enhanced DNA damage, and inhibited DNA damage repair, may be involved.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The count and classification of white blood cells (WBCs) may be used as prognostic markers in certain types of cancer. The present study investigated the prognostic potential of the counts of WBCs, ...including lymphocytes (LYs), monocytes (MOs), neutrophils (NEs), eosinophils (EOs) and basophils (BAs), in the prognosis of resectable colorectal cancer. The present study recruited 153 resectable colorectal cancer cases retrospectively, which were pathologically confirmed. All patients were divided into two groups, according to the median value of LY (low LY, ≤1.632x109/l or high LY, >1.632x109/l), MO (low MO, ≤0.330x109/l or high MO, >0.330x109/l), NE (low NE, ≤3.600x109/l or high NE, >3.600x109/l), EO (low EO, ≤0.085x109/l or high EO, >0.085x109/l), BA (low BA, ≤0.010x109/l or high BA, >0.010x109/l), or WBC (low WBC, ≤5.780x109/l or high WBC, >5.780x109/l). To evaluate the alterations in WBC counts following surgery and adjuvant chemotherapy; all samples received oxiplatin and capecitabine (XELOX) for 6‑8 cycles or 5‑fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) for 10‑12 cycles. XELOX included oxaliplatin administered intravenously at a dose of 130 mg/m2 on day 1 and 850‑1,250 mg/m2 capecitabine twice daily for days 1‑14, repeated every 3 weeks. mFOLFOX6 included oxaliplatin administered intravenously at a dose of 85 mg/m2, 400 mg/m2 leucovorin and 400 mg/m2 5‑FU on day 1 followed by 1,200 mg/m2/days continuous infusion for 2 days (in total, 2,400 mg/m2 over 46‑48 h), repeated every 2 weeks. The present study investigated the post/pre‑treatment of LY, MO, NE, EO, BA and WBC ratios (≤1 indicated that LY, MO, NE, EO, BA and WBC counts were not increased following therapy; whereas, >1 suggested increased counts). Kaplan‑Meier curves were constructed to demonstrate overall survival (OS). A multivariate and univariate logistic regression analyses model was employed to identify the independent risk factors. Low pre‑treatment BA counts were associated with larger tumor size (>5 cm); pre‑treatment BA levels were positively associated with OS. Surgery significantly decreased the count of BAs and increased the count of EOs; whereas, no effect was observed on LYs, MOs, NEs or WBCs. Adjuvant chemotherapy markedly decreased the counts of LY, NE and WBC; whereas, no notable effects on MOs, EOs or BAs were observed. Whole course treatment (surgery combined with adjuvant chemotherapy) significantly decreased the values of LY, NE and WBC; however, increased the value of EO; no effects on the MO or BA counts were observed. An increased post‑/pre‑treatment NE ratio suggested poorer prognosis. Multivariate Cox regression analysis revealed that sex, tumor size, pre‑treatment BA count and the post‑/pre‑treatment NE ratio were independent prognostic factors affecting OS. The results of the present study suggested that the pre‑treatment BA count and post‑/pre‑treatment NE ratio may be potential prognostic factors for resectable colorectal cancer.
Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in cell cycle ...control, apoptosis, and cell-fate determination. In the present study, we found that cantharidin repressed the invasive ability of pancreatic cancer cells and downregulated matrix metalloproteinase 2 (MMP2) expression through multiple pathways, including ERK, JNK, PKC, NF-κB, and β-catenin. Interestingly, transcriptional activity of the MMP2 promoter increased after treatment with PP2A inhibitors, suggesting the involvement of a posttranscriptional mechanism. By using an mRNA stability assay, we found accelerated degradation of MMP2 mRNA after treatment of cantharidin. Microarray analyses revealed that multiple genes involved in the 3' → 5' decay pathway were upregulated, especially genes participating in cytoplasmic deadenylation. The elevation of these genes were further demonstrated to be executed through ERK, JNK, PKC, NF-κB, and β-catenin pathways. Knockdown of PARN, RHAU, and CNOT7, three critical members involved in cytoplasmic deadenylation, attenuated the downregulation of MMP2. Hence, we present the mechanism of repressed invasion by cantharidin and other PP2A inhibitors through increased degradation of MMP2 mRNA by elevated cytoplasmic deadenylation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK