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Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies.

ABSTRACT: Objective: Triptolide (TL), a natural product isolated from Tripterygium wilfordii Hook F (TwHF), shows potent anticancer effects in vitro and in vivo. We aimed to summary the biochemical mechanisms through which TL has been shown to induce apoptosis, autophagy and inhibit angiogenesis in pancreatic cancer (PC). Methods: We undertook a systematic review of preclinical evidence. We searched electronic databases. The potential mechanisms and the underlying signaling pathways have been accumulated as well. Results: We screened 116 abstracts for eligibility and included 17 preclinical studies in the analysis. Details of the animals and cell lines were provided in 16 studies (94.1%). Six studies (75.0%) randomly assigned animals to treatment or control groups and only 1 study (12.5%) reported on blinding. The majority of the TL's research field has focused on its pro-apoptotic effects through downregulation of inhibitory pathways and upregulation of apoptotic pathways. The studies have shown that TL is effective both in vitro and in vivo against PC cells. Conclusion: This study provides a systematic summary of TL's anti-pancreatic cancer profile and the underlying mechanisms of with special emphasis on the apoptosis, autophagy, angiogenesis and related molecular pathways. Improved study quality in terms of treatment allocation methods reporting, randomization and blinding will accelerate needed progress toward trials.

SUBMITTER: Zhang C

PROVIDER: S-EPMC5574901 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies.

Zhang Chi C He Xiao-Juan XJ Li Li L Lu Cheng C Lu Ai-Ping AP

Frontiers in pharmacology 20170825

Objective: Triptolide (TL), a natural product isolated from Tripterygium wilfordii Hook F (TwHF), shows potent anticancer effects in vitro and in vivo. We aimed to summary the biochemical mechanisms through which TL has been shown to induce apoptosis, autophagy and inhibit angiogenesis in pancreatic cancer (PC). Methods: We undertook a systematic review of preclinical evidence. We searched electronic databases. The potential mechanisms and the underlying signaling pat ...[more]

PMID: 28890697

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Project description:BackgroundPyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated.MethodsCell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1β and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively.ResultsTriptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model.ConclusionsThis study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.

Project description:Background:Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia. It affects millions of people globally. In spite of many antidiabetic drugs that are available, an adequate level of control remains challenging. Hydroxychloroquine is an immunomodulatory drug that has been used for the treatment of malaria and autoimmune diseases. There is an emerging evidence that suggests its beneficial effect against diabetes mellitus. Therefore, this systematic review is aimed at discoursing the role of hydroxychloroquine against diabetes mellitus and its potential mechanisms of actions. Methods:A systematic and manual searching was carried out to retrieve relevant articles (preclinical and clinical studies) published from January 2014 to July 2019. Electronic databases including PubMed and Scopus as well as clinicaltrials.gov have been searched using different searching terms: "hydroxychloroquine," "diabetes mellitus," "hyperglycemia," and "insulin resistance." The MeSH terms (PubMed) and text words were combined with "AND" or "OR." In addition, manual searching of Google Engine and Google Scholar was conducted. Quality assessment of all the included studies was performed using CAMARADES (preclinical studies) and the Newcastle-Ottawa Scale and Cochrane Collaboration's tools (clinical studies). Results:A total of eighteen studies (three experimental and fifteen clinical studies) were found to be eligible for the present systematic review. Among the included clinical studies (six randomized control trials, five observational studies, and four cohort studies), about 55,776 study participants were involved. Most of these studies showed significant improvement of lipid profile and insulin levels and substantial diminution of hemoglobin A1c, fasting plasma glucose, and postprandial blood glucose levels. Reduction in lysosomal degradation of the internal insulin-insulin receptor complex and enhancement in insulin sensitivity and adiponectin levels are some of the hypothesized mechanisms for the antidiabetic effect of hydroxychloroquine. Conclusion:The current review provides preliminary evidence for potential antidiabetic properties of hydroxychloroquine. Though the provided available data were promising, further clinical trials and mechanistic studies are needed to determine its long-term effects.

Project description:Pancreatic cancer is a lethal disease with a dreadful 5-year survival rate of only 5%. In spite of several treatment options, the prognosis still remains extremely poor. Therefore, novel therapy strategies with combinations of drugs are urgently required to combat this fatal disease. Triptolide (TPL) and celastrol (CL), two main compounds in traditional Chinese medicine isolated from Thunder God Vine, have a broad range of bioactivities including anticancer activity. Silk fibroin (SF), a naturally occurring protein with several unique properties, is an ideal carrier material. In this study, we prepared TPL and CL loaded silk fibroin nanoparticles (TPL-SFNPs and CL-SFNPs) by a modified desolvation method and evaluated their synergistic effects against human pancreatic cancer cells. Both SFNPs were characterized for particle size and zeta potential. The entrapment efficiency, drug loading, and drug release profiles were evaluated by HPLC. The cytotoxicity and synergistic effect of SFNPs were investigated in MIA PaCa-2 and PANC-1 human pancreatic cells. The results showed that the particle sizes of TPL-SFNPs and CL-SFNPs were 166.4 ± 4.6 nm and 170.4 ± 2.3 nm, with a mean zeta potential -27.2 ± 2.0 mV and -25.5 ± 2.57 mV, respectively. TPL-SFNPs and CL-SFNPs have a drug loading of 57.0 ± 4.7 ?g mg-1 and 63.5 ± 3.8 ?g mg-1 along with an encapsulation efficiency of 81.8 ± 2.8% and 87.0 ± 5.1%, respectively. Drug release studies revealed that a rapid release of the drugs from SFNPs was observed at pH 4.5 (lysosomal pH) and a delayed release was observed at pH 7.4 (plasma pH). TPL-SFNPs (IC50 3.80 and 4.75 nM) and CL-SFNPs (IC50 0.38 and 0.64 ?M) were 2-3 fold more potent against MIA PaCa-2 and PANC-1 cells than free TPL (IC50 11.25 and 11.58 nM) and CL (IC50 0.84 and 1.23 ?M). Furthermore, co-treatment with TPL-SFNPs and CL-SFNPs increased the growth inhibition of the same cells significantly in comparison with TPL-SFNPs or CL-SFNPs alone. Almost all combination index (CI) values, calculated using the CompuSyn software, were <1, suggesting that the growth inhibition effect of TPL-SFNPs in combination with CL-SFNPs was synergistic rather than additive, further suggesting that this novel combination may offer a potential treatment for pancreatic cancer.

Project description:PurposeGiven the higher precision accompanied by optimized sparing of normal tissue, charged particle therapy was thought of as a promising treatment for pancreatic cancer. However, systematic preclinical studies were scarce. We aimed to investigate the radiobiological effects of charged particle irradiation on pancreatic cancer cell lines.MethodsA systematic literature search was performed in EMBASE (OVID), Medline (OVID), and Web of Science databases. Included studies were in vitro English publications that reported the radiobiological effects of charged particle irradiation on pancreatic cancer cells.ResultsThirteen carbon ion irradiation and seven proton irradiation in vitro studies were included finally. Relative biological effectiveness (RBE) values of carbon ion irradiation and proton irradiation in different human pancreatic cancer cell lines ranged from 1.29 to 4.5, and 0.6 to 2.1, respectively. The mean of the surviving fraction of 2 Gy (SF2) of carbon ion, proton, and photon irradiation was 0.18 ± 0.11, 0.48 ± 0.11, and 0.57 ± 0.13, respectively. Carbon ion irradiation induced more G2/M arrest and a longer-lasting expression of γH2AX than photon irradiation. Combination therapies enhanced the therapeutic effects of pancreatic cell lines with a mean standard enhancement ratio (SER) of 1.66 ± 0.63 for carbon ion irradiation, 1.55 ± 0.27 for proton irradiation, and 1.52 ± 0.30 for photon irradiation. Carbon ion irradiation was more effective in suppressing the migration and invasion than photon irradiation, except for the PANC-1 cells.ConclusionsCurrent in vitro evidence demonstrates that, compared with photon irradiation, carbon ion irradiation offers superior radiobiological effects in the treatment of pancreatic cancer. Mechanistically, high-LET irradiation may induce complex DNA damage and ultimately promote genomic instability and cell death. Both carbon ion irradiation and proton irradiation confer similar sensitization effects in comparison with photon irradiation when combined with chemotherapy or targeted therapy.

Project description:Some studies have reported that milk and dairy product consumption reduces bladder cancer incidence, whereas others have reported null or opposite findings. This meta-analysis of 26 cohort and case-control studies has been conducted to pool the risk of the association between milk and dairy products and bladder cancer. A systematic search in MEDLINE, EMBASE, and the Web of Science (from inception to 30 April 2018) was conducted. Random-effects models were used to compute pooled estimates of RR for high or medium compared with low consumption of milk and dairy. Sensitivity analyses were conducted. Subgroup analyses were performed based on type of dairy, gender, geographic location, and type of study design. Random-effects meta-regression was used to evaluate other confounding factors. Overall, medium compared with low consumption was associated with lower pooled risk of bladder cancer for total dairy products (RR = 0.90; 95% CI: 0.81, 0.98), milk (RR = 0.90; 95% CI: 0.82, 0.98), and fermented dairy products (RR = 0.87; 95% CI: 0.79, 0.96). The inverse association for milk consumption was stronger in Asians (RR = 0.79; 95% CI: 0.59, 0.98) and in cohort design studies (RR = 0.85; 95% CI: 0.71, 0.99). Moreover, high compared with low consumption was significantly associated with a lower pooled risk for milk (RR = 0.89; 95% CI: 0.81, 0.98) and fermented dairy products (RR = 0.78; 95% CI: 0.61, 0.94). However, high compared with low consumption of whole milk was significantly associated with a higher risk (RR = 1.21; 95% CI: 1.04, 1.38). The statistical heterogeneity was considerable. In conclusion, the present meta-analysis suggests a decreased risk of bladder cancer associated with medium consumption of total dairy products and with medium and high consumption of milk and fermented dairy products. An increased risk of bladder cancer was observed with high consumption of whole milk. Interpretations of the results should be made with caution. This review was registered at www.crd.york.ac.uk/prospero as CRD42018097020.

Dataset Information

Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies.

Publications

Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies.

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