Mitochondria-anchoring self-assembled nanoparticles for multi-path energy depletion: A "nano bomb" in chemo-co-starvation therapy.

As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid BLG@TPGS NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that Nanobomb-BLG@TPGS NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the "energy factory" mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a "three-prone strategy" to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.

Opportunities and Challenges of Nanoparticles in Digestive Tumours as Anti-Angiogenic Therapies.

Digestive tumours, a common kind of malignancy worldwide, have recently led to the most tumour-related deaths. Angiogenesis, the process of forming novel blood vessels from pre-existing vessels, is involved in various physiological and pathological processes in the body. Many studies suggest that abnormal angiogenesis plays an important role in the growth, progression, and metastasis of digestive tumours. Therefore, anti-angiogenic therapy is considered a promising target for improving therapeutic efficacy. Traditional strategies such as bevacizumab and regorafenib can target and block the activity of proangiogenic factors to treat digestive tumours. However, due to resistance and some limitations, such as poor pharmacokinetics, their efficacy is not always satisfactory. In recent years, nanotechnology-based anti-angiogenic therapies have emerged as a new way to treat digestive tumours. Compared with commonly used drugs, nanoparticles show great potential in tumour targeted delivery, controlled drug release, prolonged cycle time, and increased drug bioavailability. Therefore, anti-angiogenic nanoparticles may be an effective complementary therapy to treat digestive tumours. In this review, we outline the different mechanisms of angiogenesis, the effects of nanoparticles on angiogenesis, and their biomedical applications in various kinds of digestive tumours. In addition, the opportunities and challenges are briefly discussed.

Self-Delivered and Self-Monitored Chemo-Photodynamic Nanoparticles with Light-Triggered Synergistic Antitumor Therapies by Downregulation of HIF-1α and Depletion of GSH.

Photodynamic therapy (PDT), a clinically approved cancer treatment, has faced many drawbacks that restricted its applications. For example, the hypoxia-induced elevated hypoxia-inducible factor-1α (HIF-1α) may desensitize tumors to PDT, and the high concentration of glutathione (GSH) in cancer cells can also neutralize the generated reactive oxygen species (ROS) during PDT, resulting in insufficient therapy. Moreover, extra probes for imaging-guided visualization therapy are always needed to track drug release or distribution, while it may decrease the drug loading of the drug delivery system (DDS). In the present study, we have designed and prepared a novel multifunctional combined therapy nanoparticle (ZnPc@Cur-S-OA NPs), in which curcumin (Cur) was not only used as a chemotherapy drug to achieve a combination therapy with PDT via downregulating HIF-1α and depleting GSH in B16F10 cells but also designed as a small-molecule ROS-triggered release prodrug to deliver the photosensitizer (PS). The red fluorescence of PS in the nanoparticles (NPs) can be used to track the NPs distribution, while the green fluorescence of Cur showed an "OFF-ON" activation, which enables additional imaging and real-time self-monitoring capabilities. These results proved that the prepared combined therapy NPs were more effective to inhibit the growth of B16F10 mouse melanoma tumor than was monotherapy without eliciting systemic toxicity either in vitro or in vivo, which indicated the combined therapy NPs as an effective way to improve the PDT efficacy via downregulation of HIF-1α and depletion of GSH. Thus, the strategy of using a multifunctional natural product as the stimuli-responsive carrier as well as the synergist with PDT for enhancing antitumor efficacy via multiple pathways may open an alternative avenue to fabricate new self-delivery combination therapy nanodrugs. Besides, the fluorescence emitted from the drug can be used for real-time self-monitoring of drug release and distribution, which has great potential in clinic to adjust the administration dose and irradiation time for different tumor types and stages for individual therapy.

BHQ-Cyanine-Based "Off-On" Long-Circulating Assembly as a Ferroptosis Amplifier for Cancer Treatment: A Lipid-Peroxidation Burst Device.

Ferroptosis is an iron-dependent cell death caused by accumulation of lipid peroxidation (LPO), which is a new strategy for cancer treatment. Th current ferroptosis therapy nanodevices have low efficiency and side effects generally. Hence, we developed a Black Hole Quencher (BHQ)-based fluorescence "off-on" nanophotosensitizer complex assembly (CSO-BHQ-IR780-Hex/MIONPs/Sor). CSO-connected BHQ-IR780-Hex and -loaded magnetic iron oxide nanoparticles (MIONPs) and sorafenib (Sor) formed a very concise functionalized delivery system. CSO-BHQ-IR780-Hex disassembled by GSH attack and released IR780-Hex, MIONPs, and sorafenib. IR780-Hex anchored to the mitochondrial membrane, which would contribute to amplifying the efficiency of the photosensitizer. When NIR irradiation was given to CSO-BHQ-IR780-Hex/MIONPs/Sor-treated cells, iron supply increased, the xCT/GSH/GPX-4 system was triggered, and a lot of LPO burst. A malondialdehyde test showed that LPO in complex assembly-treated cells was explosive and increased about 18-fold compared to the control. The accumulation process of particles was monitored by an IR780-Hex photosensitizer, which showed an excellent tumor target ability by magnetic of nanodevice in vivo. Interestingly, the half-life of sorafenib in a nanodevice was increased about 26-fold compared to the control group. Importantly, the complex assembly effectively inhibits tumor growth in the breast tumor mouse model. This work would provide ideas in designing nanomedicines for the ferroptosis treatment of cancer.

Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer.

Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst. Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies. Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment. Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.

Comparative efficacy of non-pharmacological adjuvant therapies for quality of life in the patients with breast cancer receiving chemo- or radio-therapy: A protocol for systematic review and Bayesian network meta-analysis.

BACKGROUND: Breast cancer is the most frequently diagnosed cancer in women worldwide. When treated by chemotherapy and/or radiotherapy, there are various non-pharmacological adjuvant therapies (NPATs) recommended for helping the patients with breast cancer alleviate multiple side effects induced by chemotherapy and/or radiotherapy and improve quality of life (QoL). However, the existing evidence does not suggest the therapy with the best effectiveness among a variety of NPATs. This study is to compare the effectiveness of different NPATs on QoL in the patients with breast cancer using Bayesian network meta-analysis (NMA). METHODS AND ANALYSIS: We will conduct a comprehensive search strategy in the relevant databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, World Health Organization (WHO), International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx), Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wan Fang Data). The random or quasi-random controlled trails that compare different NPATs in patient with breast cancer who received the chemotherapy and/or radiotherapy will be included. We only focus on the outcome of QoL which can be assessed by a series of tools. The risk of bias for included studies will be appraised using the Cochrane Collaboration's tool for assessing risk of bias. The standard pairwise meta-analysis and a Bayesian NMA will be conducted. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required since this is an NMA based on published studies. We will submit our NMA to a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42017078143.

Coffee consumption and the risk of incident gastric cancer--A meta-analysis of prospective cohort studies.

As several epidemiological studies on the association of coffee consumption with gastric cancer risk have produced inconsistent results, this meta-analysis was designed to synthesize current evidence of this potential relationship. We searched PubMed, EMBASE, and the Cochrane Library up to September 2014 to retrieve relevant articles. Prospective cohort studies were included if the relative risks (RRs) or hazard ratios and 95% confidence intervals (CIs) for gastric cancer according to coffee consumption were reported. Fixed- or random-effects models were used based on heterogeneity. The search yielded 13 eligible cohort studies of 3484 incident gastric cancer patients from among 1,324,559 participants. A significantly increased risk was found between gastric cardia cancer and coffee consumption (RR = 1.50, 95% CI: 1.09-2.07). Compared with Europeans (RR = 1.12, 95% CI: 0.86-1.46) and Asians (RR = 0.96, 95% CI: 0.72-1.27), Americans (RR = 1.36, 95% CI: 1.06-1.74) demonstrated a significantly positive association. However, the significant differences of the pooled results vanished after adjusting for smoking or body mass index. Our meta-analysis results suggest that a high level of coffee consumption is a risk factor for gastric cancer. However, these results should not be overinterpreted because residual confounding effects of other factors could exist.

S100P enhances the chemosensitivity of human gastric cancer cell lines.

BACKGROUND: The effect of the protein S100P on biological characteristics of cancer is not clear, especially in gastric cancer. We previously showed that S100P positive gastric cancer patients have a better cumulative survival than S100P negative patients. OBJECTIVE: To study the possible mechanisms of S100P enhanced the chemosensitivity to oxaliplatin in gastric cancer cell lines. METHODS: S100P was overexpressed in vitro by plasmid transfection and downregulated by siRNA transfection in the BGC823 and SGC7901 gastric cancer cell lines. Cell survival rate, changes in the chemoresistance gene, such as GST-π, MDR1, MRP1, Topo-II, MVP and BCRP, intake of anticancer drug were measured after oxaliplatin treatment. RESULTS: In SGC7901 cells, MTT assay indicated that increased S100P expression levels decreased the survival rate and decreased S100P expression levels increased the survival rate. In BGC823 and SGC7901 cell lines, mRNA of MDR1, a chemoresistance genes, was decreased in cells that overexpressed S100P, and increased in cells with downregulation of S100P. Intracellular accumulation of platinum increased in cells with overexpressed S100P, and decreased in cells with S100P downregulation. CONCLUSIONS: S100P contributes to oxaliplatin chemosensitivity in gastric cell lines by increasing drug inflow. It might also be a novel independent prognostic factor in gastric cancer patients who receive adjuvant chemotherapy with oxaliplatin.

[Impact of S100P expression on clinical outcomes of gastric cancer patients with adjuvant chemotherapy of oxaliplatin and its mechanisms].

OBJECTIVE: To investigate the impact of the expression of S100P on the prognosis and tumor chemosensitivity in patients with resectable gastric cancer and its mechanisms. METHODS: The expression of S100P was analyzed in 121 resected primary gastric cancer tissues by using tissue array of immunohistochemistry excised from January 2003 to December 2007. The patients received adjuvant chemotherapy with oxaliplatin. The pEGFP-S100P plasmid was constructed and was transfected into BGC823 cell line to establish gastric cancer cell line with over-expression of human S100P, BGC823-S100P. The expression level of S100P was determined by real-time PCR and Western blot assay. The chemosensitivity of BGC823-S100P cell line to oxaliplatin was detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. RESULTS: The S100P was positively expressed in 64 tumors (52.9%, 64/121). Although there was no significant relation between the expression of S100P and tumor T staging (P = 0.683), N staging (P = 0.472), M staging (P = 0.770) and differentiation (P = 0.553), Wilcoxon test showed that the 5-year cumulative survival rate of patients with positive S100P expression was significantly higher than that of patients with negative expression (20.3% vs. 3.5%, P = 0.034). Furthermore, overexpressed of S100P was found in the BGC823 cell line, BGC823-S100P. The mRNA and protein level of S100P in pEGFP transfected BGC823-S100P cell lines were significantly higher than those in control group (8.42 ± 1.38 vs. 0.83 ± 0.11 and 3.52 ± 0.48 vs. 0.97 ± 0.19, all P < 0.05). It indicated with MTT assay that the half-inhibitory concentration (IC(50)) to oxaliplatin decreased in BGC823-S100P cells, and was significantly lower than that in vector-only transfected cells [(142 ± 16) mg/L vs. (266 ± 11) mg/L, P = 0.032]. CONCLUSIONS: S100P may also be a potentially novel independent prognostic factor in gastric cancer patients following curative resection. And it could improve the cumulative survival of the patients through enhancing the chemosensitivity of tumor cell line to oxaliplatin.

Sodium butyrate induces differentiation of gastric cancer cells to intestinal cells via the PTEN/phosphoinositide 3-kinase pathway.

NaB (sodium butyrate) inhibits cell proliferation and induces differentiation in a variety of tumour cells. In this study, we aimed to determine whether NaB induced differentiation and regulated the expression of the mucosal factor MUC2 through the PTEN/PI3K (phosphoinositide 3-kinase) pathway. BGC823 cells treated with NaB for 24-72 h showed marked inhibition of cell proliferation and alteration in cellular morphology. NaB treatment markedly increased the expression of PTEN and MUC2, but it decreased the expression of PI3K. These effects were enhanced by intervention with PI3K inhibitors and were reduced by intervention with PTEN siRNA. Hence, we conclude that NaB increased PTEN expression, promoted the expression of MUC2 and induced the differentiation of gastric cancer cells through the PTEN/PI3K signalling pathway.

Identification and purification of resveratrol targeting proteins using immobilized resveratrol affinity chromatography.

The phytochemical resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenol with a plethora of health-beneficial properties, including a preventive role in cancer. We surmise that resveratrol may exert its diverse biological effects by interacting with specific target proteins, denoted RTPs. To test this possibility, resveratrol was immobilized on epoxy-activated agarose forming a resveratrol affinity column (RAC), which was used to detect and isolate RTPs. Distinct RTPs can be resolved on RAC by fractionation with increasing NaCl, followed by 1mM ATP, and finally, with 1-2mM resveratrol. A 22-kDa polypeptide, RTP-22, eluted with resveratrol was identified by MALDI-TOF MS and cloning/expression in Escherichia coli, as dihydronicotinamide riboside quinone reductase 2 (NQO2). The utility of RAC was additionally explored with extracts derived from different staging prostate cancer cells. NQO2 was most abundant in CWR22Rv1, a model for prostate cancer transition from androgen-dependent to the hormone-refractory state, but was marginally expressed in JCA-1 cells as representing more advanced stage prostate cancer. These results provide evidence for the existence of distinctive RTPs in mammalian cells and that RAC is a facile approach to identify and purify RTPs.