Publications by authors named "Ming Q Wei"

62 Publications

Immunotherapy for non-small cell lung cancer (NSCLC), as a stand-alone and in combination therapy.

Crit Rev Oncol Hematol 2021 Aug 7;164:103417. Epub 2021 Jul 7.

Menzies Health Institute Queensland and School of Medical Science, Griffith University, Gold Coast Campus, Parklands Drive, Southport, QLD, 4215, Australia.

Non-small cell lung cancer (NSCLC) is of major concern for society as it is associated with high mortality and is one of the most commonly occurring of all cancers. Due to the number of mutational variants and general heterogeneity of this type of cancer, treatment using conventional modalities has been challenging. Therefore, it is important to have improved therapeutic treatments like immunotherapy, that can specifically treat the disease while causing minimal damage to healthy tissue and additionally provide systemic immunity. Cancer vaccines are an important element of cancer immunotherapy and have been approved for treatment of a limited number of cancers, including NSCLC. This article highlights scientific evidence for several therapeutic treatment strategies for NSCLC, alone or in combination, which offers new hope for those suffering. Although cancer vaccines have had some success as a monotherapy, their potential in a combination therapy needs to be critically analyzed for future applications.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103417DOI Listing
August 2021

Host-Defense Peptides Caerin 1.1 and 1.9 Stimulate TNF-Alpha-Dependent Apoptotic Signals in Human Cervical Cancer HeLa Cells.

Front Cell Dev Biol 2020 31;8:676. Epub 2020 Jul 31.

Genecology Research Centre, University of the Sunshine Coast, Maroochydore, QLD, Australia.

Host defense caerin 1.1 and 1.9 peptides, isolated from the glandular secretion of Australian tree frogs, the genus , have been previously shown to have multiple biological activities, including the inhibition of human papillomavirus (HPV) 16 early protein E7 transformed murine as well as human cancerous cell proliferation both and . However, the mechanism underlying their anti-proliferative activities against HPV18+ cervical cancer HeLa cells remains unknown. This study comparatively investigated the anti-proliferation on HeLa cells by caerin 1.1, 1.9, and their mixture, followed by confocal microscopy examination to assess the cellular intake of the peptides. Tandem mass tag labeling proteomics was employed to reveal the proteins that were significantly regulated by the peptide treatment in cells and cell growth environment, to elucidate the signaling pathways that were modulated. Western blot was performed to confirm the modulation of the pathways. Both caerin 1.1 and 1.9 highly inhibited HeLa cell proliferation with a significant additive effect compared to untreated and control peptide. They entered the cells with different magnitudes. Intensive protein-protein interaction was detected among significantly upregulated proteins. Translation, folding and localization of proteins and RNA processing, apoptosis process was significantly enriched post the treatments. The apoptotic signaling was suggested as a result of tumor necrosis factor-α (TNF-α) pathway activation, indicated by the dose-dependent elevated levels of caspase 3 and caspase 9. The epidermal growth factor receptor and androgen receptor pathways appeared inhibited by the peptides. Moreover, the activation of T-cell receptor derived from the quantitation results further implies the likelihood of recruiting more T cells to the cell growth environment post the treatment and more sensitive to T cell mediated killing of HeLa cells. Our results indicate that caerin 1.1 and 1.9 mediate apoptotic signals of HeLa cells and may subsequently enhances adaptive T cell immune responses.
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http://dx.doi.org/10.3389/fcell.2020.00676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412766PMC
July 2020

Significance of LL-37 on Immunomodulation and Disease Outcome.

Biomed Res Int 2020 16;2020:8349712. Epub 2020 May 16.

School of Medical Science & Menzies Health Institute Queensland, Griffith University, Gold Coast, Qld 4215, Australia.

LL-37, also called cathelicidin, is an important part of the human immune system, which can resist various pathogens. A plethora of experiments have demonstrated that it has the multifunctional effects of immune regulation, in addition to antimicrobial activity. Recently, there have been increasing interest in its immune function. It was found that LL-37 can have two distinct functions in different tissues and different microenvironments. Thus, it is necessary to investigate LL-37 immune functions from the two sides of the same coin. On the one side, LL-37 promotes inflammation and immune response and exerts its anti-infective and antitumor effects; on the other side, it has the ability to inhibit inflammation and promote carcinogenesis. This review presents a brief summary of its expression, structure, and immunomodulatory effects as well as brief discussions on the role of this small peptide as a key factor in the development and treatment of various inflammation-related diseases and cancers.
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http://dx.doi.org/10.1155/2020/8349712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246396PMC
March 2021

Salivary microRNA miR-let-7a-5p and miR-3928 could be used as potential diagnostic bio-markers for head and neck squamous cell carcinoma.

PLoS One 2020 24;15(3):e0221779. Epub 2020 Mar 24.

School of Dentistry and Oral Health, Griffith University Gold Coast, Queensland, Australia.

Backgrounds: MicroRNAs (miRNA) are a class of non-protein-coding RNAs that have significant biological and pathological functions. The importance of miRNAs as potential cancer diagnostic biomarkers is gaining attention due to their influence in the regulation of cellular processes such as cell differentiation, proliferation and apoptosis. The aim of this study was to identify significant miRNAs from saliva as potential diagnostic biomarkers in the early diagnosis and prognosis of head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: Five differentially expressed miRNAs (miR-7703, miR- let-7a-5p, miR- 345-5p, miR- 3928 and miR- 1470) were selected from Next Generation Sequencing (NGS) miRNA data generated from our previous study using saliva of 12 HNSCC patients and 12 healthy controls. Their differential expressed miRNAs were subsequently validated by RT-qPCR using saliva samples from healthy controls (n = 80) and HNSCC patients (n = 150). Total RNA was isolated from 150 saliva samples of HNSCC patients and was transcripted into cDNA by TaqMan MicroRNA Reverse Transcription Kit. Using quantitative RT-PCR analysis, salivary miRNAs were identified in HNSCC patients (n = 150) and healthy controlled cases (n = 80). T-tests were used to compare the differences among the various clinical variants.

Results: On average 160 ng/μl was isolated from 500 μl of saliva. Overall, a good correlation observed between the HNSCC and some of miRNAs expression levels. Salivary miR-let-7a-5p (P<0.0001) and miR-3928 (P< 0.01) were significantly down regulated in saliva of HNSCC patients relative to age and sex-matched healthy controls. A number of salivary miRNAs (miR-let-7a-5p and miR-3928) were correlated with lymph node metastasis (p = 0.003, p = 0.049) and tumour size (p = 0.01, p = 0.02), respectively. However, our preliminary analysis showed no significant differences in salivary miR-1470, miR-345-5p or miR-7703 expression between patients and healthy controls. Most notably, our analysis showed that salivary miR-let-7a-5p and miR-3928 expression levels have significant sensitivity and specificity to distinguish between patients with HNSCC and healthy controls.

Conclusion: This study concluded that salivary miR-let-7a-5p and miR-3928 has the potential to be novel non-invasive biomarkers for early detection and prognosis of HNSCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221779PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092992PMC
May 2020

Therapeutic Effects of Ten Commonly Used Chinese Herbs and Their Bioactive Compounds on Cancers.

Evid Based Complement Alternat Med 2019 15;2019:6057837. Epub 2019 Sep 15.

School of Medical Science & Menzies Health Institute Queensland, Griffith University, Brisbane, Australia.

Effective cancer therapy is one of the biggest global challenges. Conventional cancer therapies have been at the forefront of combating cancers, but more evidence showed considerable side effects, limiting their use. There are various new therapies in development, but combined approaches for treating cancer are much expected. Natural herbs had been traditionally in use for cancer therapy in most parts of the world. In this review, we have examined ten commonly used Chinese herbs that have, for centuries, shown effectiveness in treating cancers. They demonstrated the abilities to promote the apoptosis of cancer cells, inhibit their metastasis, activate the patient's anticancer immunity, and synergistically increase the efficacy of conventional chemotherapy and radiation therapy when used in combination. Clinical experiences had proved that these herbs and their bioactive compounds were effective against a plethora of cancers through a variety of mechanisms, effectively improving patients' quality of life without significant side effects. These advantages indicate that there are huge potentials in the development of Chinese herbs into cancer medicine as part of a promising, holistic cancer treatment modality.
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http://dx.doi.org/10.1155/2019/6057837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766161PMC
September 2019

Cripto-1 overexpression in U87 glioblastoma cells activates MAPK, focal adhesion and ErbB pathways.

Oncol Lett 2019 Sep 16;18(3):3399-3406. Epub 2019 Jul 16.

Division of Molecular and Gene Therapies, School of Medical Science, Griffith University, Gold Coast, Queensland 4222, Australia.

Discovering the underlying signalling pathways that control cancer cells is crucial for understanding their biology and to develop therapeutic regimens. Thus, the aim of the present study was to determine the effect of Cripto-1 on pathways controlling glioblastoma (GBM) cell function. To this end, changes in protein phosphorylation in cells overexpressing Cripto-1 were analysed using the Kyoto Encyclopedia of Genes and Genomes pathway analysis tool, as well as the Uniprot resource to identify the functions of Cripto-1-dependent phosphorylated proteins. This revealed that proteins affected by Cripto-1 overexpression are involved in multiple signalling pathways. The mitogen-activated protein kinase (MAPK), focal adhesion (FA) and ErbB pathways were found to be enriched by Cripto-1 overexpression with 35, 27 and 24% of pathway proteins phosphorylated, respectively. These pathways control important cellular processes in cancer cells that correlate with the observed functional changes described in earlier studies. More specifically, Cripto-1 may regulate MAPK cellular proliferation and survival pathways by activating epithelial growth factor receptor (EGFR; Ser1070) or fibroblast GFR1 (Tyr654). Its effect on cellular proliferation and survival could be mediated through Src (Tyr418), FA kinase (FAK; Tyr396), p130CAS (Tyr410), c-Jun (Ser63), Paxillin (PXN; Tyr118) and BCL2 (Thr69) of the FA pathway. Cripto-1 may also control cellular motility and invasion by activating Src (Tyr418), FAK (Tyr396) and PXN (Tyr118) of the FA pathway. However, Cripto-1 regulation of cellular invasion and migration might be not limited to the FA pathway, it may also control these cellular mechanisms through signalling via EGFR (Ser1070)/Her2 (Tyr877) to mediate the Src (Tyr418) and FAK (Tyr396) cascade activation of the ErbB signalling pathway. Angiogenesis could be mediated by Cripto-1 by activating c-Jun (Ser63) through EGFR (Ser1070)/Her2 (Tyr877) of the ErbB pathway. To conclude, the present study has augmented and enriched our current knowledge on the crucial roles that Cripto-1 may play in controlling different cellular mechanisms in GBM cells.
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http://dx.doi.org/10.3892/ol.2019.10626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676405PMC
September 2019

miR-496, miR-1185, miR-654, miR-3183 and miR-495 are downregulated in colorectal cancer cells and have putative roles in the mTOR pathway.

Oncol Lett 2019 Aug 21;18(2):1657-1668. Epub 2019 Jun 21.

Division of Molecular and Gene Therapies, School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by suppressing the target mRNA and inhibiting translation in order to regulate multiple biological processes. miRNAs play important roles as oncogenes or tumor suppressors in the development of various types of human cancer. The regulation of mammalian target of rapamycin (mTOR) by miRNAs has been studied in several types of cancer, including colorectal cancer (CRC). However, to the best of our knowledge, only limited information regarding the function of miRNAs in human CRC is available. In the present study, the expression of 22 miRNAs in CRC cell lines were investigated in regard to key genes in the mTOR pathway. Initially, it was revealed that mTOR, regulatory-associated protein of mTOR complex I and rapamycin-intensive companion of mTOR were overexpressed in CRC cell lines when compared with a normal colorectal cell line. Subsequently, putative miRNA-mRNA associations were identified via multiple miRNA target prediction programs. The expression levels for the candidate miRNAs were validated using quantitative real-time polymerase chain reaction. Expression analysis revealed that, among 20 miRNAs, five miRNAs (miR-496, miR-1185, miR-654, miR-3183 and miR-495) exhibited significant downregulation in association with the mTOR signaling pathway. Taken together, the results from the present study suggest that several miRNAs that are associated with CRC, with possible roles in mTOR signaling, may have potential therapeutic or diagnostic benefits in CRC treatment.
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http://dx.doi.org/10.3892/ol.2019.10508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614670PMC
August 2019

Vaccinations for Colorectal Cancer: Progress, Strategies, and Novel Adjuvants.

Int J Mol Sci 2019 Jul 11;20(14). Epub 2019 Jul 11.

School of Medical Science and Menzies Health Institute Queensland, Gold Coast campus, Griffith University, Southport, QLD 4222, Australia.

Although cancer is a leading cause of death, significant breakthroughs have been made in its treatment in recent years. In particular, increasingly effective cancer vaccines are being developed, including some for colorectal cancer. There are also currently a variety of compounds that can act as adjuvants, such as signalling molecules called cytokines. Other adjuvants target and inhibit the specific mechanisms by which cancers evade the immune system. One of them is a galectin inhibitor, which targets galectins-proteins produced by cancer cells that can cause the death of immune cells. Likewise, immune checkpoint inhibitors affect immune checkpoints-natural host proteins that usually control inflammation but can be exploited by cancers to weaken the body's defences. Equally, regulatory T cells may contribute to the progression of cancer by inhibiting the functions of other T cells. The main advantages of cancer vaccines include their low toxicity and their ability to strengthen the immune system. Nevertheless, significant limitations include their slow effects and their inability to treat cancer at times due to immunosuppression. Ultimately, ongoing trials provide hope for the development of more effective methods of immunotherapeutic inoculation that can target a greater variety of cancers.
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http://dx.doi.org/10.3390/ijms20143403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678766PMC
July 2019

The Dosage of the Derivative of (DCG) Spores Dictates Whether an IFN/IL-9 or a Strong IFN Response Is Elicited in TC-1 Tumour Bearing Mice.

Biomed Res Int 2019 28;2019:1395138. Epub 2019 Apr 28.

School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4333, Australia.

Background: Anaerobic spores (CG) cause significant oncolysis in hypoxic tumour microenvironment and result in tumour regression in both animal models and clinical trials. The immune mediated response plays a critical role in the antitumour effect by the anaerobic spore treatment.

Method: Human papillomavirus 16 E6/E7 transformed TC-1 tumour bearing mice were intravenously administered with low (1 × 10 CFU/kg) or high dosage (3 × 10 CFU/kg) of Derivative spore (DCG).

Results: Intravenous administration of the derivative of (DCG) spores leads to both tumour and systemic inflammatory responses characterized by increased IFN/IL-9 secreting T cells in the spleen and the tumour. Low numbers of antigen specific T cells (<20/10 spleen cells) in the spleen of the tumour bearing mice are also detected after intravenous DCG delivery. Interestingly, our results showed that a mixed IL-9/IFN secreting T cell response was induced when the tumour bearing mice received a low dose of DCG spore (1 × 10 CFU/kg), while a strong IFN response was elicited with a high dosage of DCG spore (3 × 10 CFU/kg).

Conclusion: The dosage of DCG spore will determine the types of the DCG induced immune responses.
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http://dx.doi.org/10.1155/2019/1395138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512072PMC
December 2019

Encapsulation of Plasmid DNA by Nanoscale Metal-Organic Frameworks for Efficient Gene Transportation and Expression.

Adv Mater 2019 Jul 3;31(29):e1901570. Epub 2019 Jun 3.

Key Laboratory of Nanosystem and Hierarchical Fabrication, Chinese Academy of Sciences, National Center for Nanoscience and Technology, No.11, Beiyitiao, Zhongguancun, Beijing, 100190, P. R. China.

The intracellular delivery and functionalization of genetic molecules play critical roles in gene-based theranostics. In particular, the delivery of plasmid DNA (pDNA) with safe nonviral vectors for efficient intracellular gene expression has received increasing attention; however, it still has some limitations. A facile one-pot method is employed to encapsulate pDNA into zeolitic imidazole framework-8 (ZIF-8) and ZIF-8-polymer vectors via biomimetic mineralization and coprecipitation. The pDNA molecules are found to be well distributed inside both nanostructures and benefit from their protection against enzymatic degradation. Moreover, through the use of a polyethyleneimine (PEI) 25 kD capping agent, the nanostructures exhibit enhanced loading capacity, better pH responsive release, and stronger binding affinity to pDNA. From in vitro experiments, the cellular uptake and endosomal escape of the protected pDNA are greatly improved with the superior ZIF-8-PEI 25 kD vector, leading to successful gene expression with high transfection efficacy, comparable to expensive commercial agents. New cost-effective avenues to develop metal-organic-framework-based nonviral vectors for efficient gene delivery and expression are provided.
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http://dx.doi.org/10.1002/adma.201901570DOI Listing
July 2019

Comparative proteomic study reveals the enhanced immune response with the blockade of interleukin 10 with anti-IL-10 and anti-IL-10 receptor antibodies in human U937 cells.

PLoS One 2019 21;14(3):e0213813. Epub 2019 Mar 21.

Genecology Research Centre, University of the Sunshine Coast, Maroochydore DC, Australia.

Blocking cytokine interleukin 10 (IL-10) at the time of immunisation enhances vaccine induced T cell responses and improves control of tumour cell growth in vivo. However, the effect of an IL-10 blockade on the biological function of macrophages has not been explored. In the current paper, a macrophage precursor cell line, U937 cells, was selected to investigate the differential expression of proteins and relevant cell signalling pathway changes, when stimulated with lipopolysaccharide (LPS) in the presence of antibodies to IL-10 or IL-10 receptor. We used a quantitative proteomic strategy to investigate variations in protein profiles of U937 cells following the treatments with LPS, LPS plus human anti-IL10 antibody and anti-IL10R antibody in 24hrs, respectively. The LPS treatment significantly activated actin-related cell matrix formation and immune response pathways. The addition of anti-IL10 and anti-IL10R antibody further promoted the immune response and potentially effect macrophage survival through PI3K/AKT signalling; however, the latter appeared to also upregulated oncogene XRCC5 and Cajal body associated processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428271PMC
December 2019

EGFR and Prion protein promote signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in colorectal cancer.

Mol Oncol 2019 04 8;13(4):725-737. Epub 2019 Feb 8.

Tumour Microenvironment Lab, QIMR Berghofer Medical Research Institute, Herston, Australia.

Epidermal growth factor receptor (EGFR) supports colorectal cancer progression via oncogenic signaling. Anti-EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that PrP expression levels may regulate EGFR signaling and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of PrP or inhibition of EGFR signaling via gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to cisplatin. Expression of these proteins was examined in matched primary and metastatic patient samples and was correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of PrP and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that PrP contributed to signaling via colocalization with EGFR, which could be overcome by targeting p38 mitogen-activated protein kinases (p38 MAPK). We revealed that the level of Krüppel-like factor 5 (KLF5), a target downstream of p38 MAPK, was predictive for cell line and patient response to platinum agents. Further, high KLF5 expression was observed in BRAF-mutant colorectal cancer. Our study indicates that the EGFR to KLF5 pathway is predictive of patient progression on platinum-based therapy.
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http://dx.doi.org/10.1002/1878-0261.12411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441932PMC
April 2019

EGF ligand fused to truncated Pseudomonas aeruginosa exotoxin A specifically targets and inhibits EGFR‑positive cancer cells.

Oncol Rep 2018 Nov 6;40(5):2690-2697. Epub 2018 Sep 6.

School of Medical Science and Menzies Health Institute Queensland, Griffith University, Southport, Gold Coast, QLD 4215, Australia.

Cancer cells have been known to overexpress the epidermal growth factor receptor (EGFR) and hence relevant multiple‑targeted therapies have been developed, with a recent clinical application of the antibody‑mediated inhibition of the EGFR. However, this strategy is not useful in cancer cells with mutations in KRAS; a GTPase downstream of EGFR which constitutively activates the pathway without EGF stimulation. Furthermore, mutations in EGFR also reduce the binding of monoclonal antibodies and thereby render them ineffective. In the present study, we designed a chimeric EGF protein fused to the truncated N‑terminal domain fragment of Pseudomonas aeruginosa exotoxin A (EGF‑ETA), which has ADP‑ribosylation activity and induces apoptosis. The EGF‑ETA protein was expressed in E. coli as a His‑tagged fusion. Our results showed that EGF‑ETA significantly inhibited the proliferation of EGFR‑positive A431 epidermoid carcinoma (IC50 27 ng/ml) and HN5 head and neck squamous cell carcinoma (IC50 36 ng/ml) cells. However, its effect on cancer cells with little or no EGFR expression was limited (A549‑IC50 1,000 ng/ml; MCF‑7‑IC50 >10,000 ng/ml). Compared to cetuximab, EGF‑ETA was highly potent in its killing capacity of HN5 cancer cells at 1,000 ng/ml, while cetuximab had little effect at 1,000 ng/ml. Furthermore, EGF‑ETA was just as potent in HCT116 (KRAS G13D) and SW480 (KRAS G12V) colon cancer cell lines harbouring KRAS hyperactivating mutations when compared to KRAS wild‑type HT29 colon cancer cells. Finally, co‑incubation of EGF‑ETA with an anti‑EGF antibody abrogated its effect on the EGFR‑positive A431 cells. Our results show that the chimeric EGF‑ETA toxin is extremely effective against EGFR‑positive cancers and raises the potential to further develop this chimera for use in targeting EGFR‑positive tumours resistant to monoclonal antibodies.
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http://dx.doi.org/10.3892/or.2018.6685DOI Listing
November 2018

The Development of Toad Toxins as Potential Therapeutic Agents.

Toxins (Basel) 2018 08 20;10(8). Epub 2018 Aug 20.

Menzies Health Institute Queensland and School of Medical Science, Griffith University, Gold Coast, QLD 4222, Australia.

Toxins from toads have long been known to contain rich chemicals with great pharmaceutical potential. Recent studies have shown more than 100 such chemical components, including peptides, steroids, indole alkaloids, bufogargarizanines, organic acids, and others, in the parotoid and skins gland secretions from different species of toads. In traditional Chinese medicine (TCM), processed toad toxins have been used for treating various diseases for hundreds of years. Modern studies, including both experimental and clinical trials, have also revealed the molecular mechanisms that support the development of these components into medicines for the treatment of inflammatory diseases and cancers. More recently, there have been studies that demonstrated the therapeutic potential of toxins from other species of toads, such as Australian cane toads. Previous reviews mostly focused on the pharmaceutical effects of the whole extracts from parotoid glands or skins of toads. However, to fully understand the molecular basis of toad toxins in their use for therapy, a comprehensive understanding of the individual compound contained in toad toxins is necessary; thus, this paper seeks to review the recent studies of some typical compounds frequently identified in toad secretions.
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http://dx.doi.org/10.3390/toxins10080336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115759PMC
August 2018

Comparative Proteomic Study of the Antiproliferative Activity of Frog Host-Defence Peptide Caerin 1.9 and Its Additive Effect with Caerin 1.1 on TC-1 Cells Transformed with HPV16 E6 and E7.

Biomed Res Int 2018 13;2018:7382351. Epub 2018 May 13.

Genecology Research Centre, University of the Sunshine Coast, Maroochydore, QLD 4558, Australia.

Caerin is a family of peptides isolated from the glandular secretion of Australian tree frogs, the genus , and has been previously shown to have anticancer activity against several cancer cells. In this work, we used two host-defence peptides, caerin 1.1 and caerin 1.9, to investigate their ability to inhibit a murine derived TC-1 cell transformed with human papillomavirus 16 E6 and E7 growth . Caerin 1.9 inhibits TC-1 cell proliferation, although inhibition is more pronounced when applied in conjunction with caerin 1.1. To gain further insights into the antiproliferative mechanisms of caerin 1.9 and its additive effect with caerin 1.1, we used a proteomics strategy to quantitatively examine (i) the changes in the protein profiles of TC-1 cells and (ii) the excretory-secretory products of TC-1 cells following caerin peptides treatment. Caerin 1.9 treatment significantly altered the abundance of several immune-related proteins and related pathways, such as the Tec kinase and ILK signalling pathways, as well as the levels of proinflammatory cytokines and chemokines. In conclusion, caerin peptides inhibit TC-1 cell proliferation, associated with modification in signalling pathways that would change the tumour microenvironment which is normally immune suppressive.
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http://dx.doi.org/10.1155/2018/7382351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971270PMC
October 2018

Dual mTOR/PI3K inhibitor NVP‑BEZ235 arrests colorectal cancer cell growth and displays differential inhibition of 4E‑BP1.

Oncol Rep 2018 Aug 22;40(2):1083-1092. Epub 2018 May 22.

School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland 4333, Australia.

The mammalian target of rapamycin (mTOR), a downstream effector of the PI3K/Akt signalling pathway, is a critical regulator of cell metabolism, growth and survival in response to oncogenic factors. Activation of mTOR frequently occurs in human tumours making it a crucial and validated target in the treatment of cancer. mTOR inhibitors such as rapamycin and its analogues decrease cancer progression in experimental models including colorectal cancer (CRC). Recently, the second generation ATP‑competitive mTOR kinase (such as PP242) and dual mTOR/PI3K (such as NVP‑BEZ235) inhibitors have entered clinical trials as anticancer agents. However, in CRC, the efficacy of these novel drugs needs to be fully investigated. In the present study, we examined five human CRC cell lines, HT29, HCT116, SW480, SW620 and CSC480 to evaluate their sensitivity to three mTOR inhibitors, RAD001, PP242 and NVP‑BEZ235. We observed that compared to RAD001 and PP242, NVP‑BEZ235 markedly reduced cell proliferation of CRC cells. Furthermore, we found that the reduced cell proliferation caused by NVP‑BEZ235 was not achieved through the disruption of mitochondrial potential. Using an mTOR‑specific signalling pathway phospho array we revealed that NVP‑BEZ235 significantly decreased phosphorylation of 4E‑BP1 (Thr70), the downstream target of mTORC1. In addition, NVP‑BEZ235 decreased phosphorylation of AKT (Ser473), the downstream target of mTORC2. Immunoblotting analysis revealed that NVP‑BEZ235 effectively inhibited 4E‑BP1 phosphorylation, while PP242 had a weak inhibitory effect. However, PP242 and NVP‑BEZ235 decreased AKT levels in all cell lines. RAD001 demonstrated no effect on 4E‑BP1. Based on the above‑mentioned results, the dual PI3K/mTOR and ATP‑competitive mTOR inhibitors have demonstrated high potential for targeting the mTOR pathway in CRC.
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http://dx.doi.org/10.3892/or.2018.6457DOI Listing
August 2018

A Simple Glycolipid Mimic of the Phosphatidylinositol Mannoside Core from Mycobacterium tuberculosis Inhibits Macrophage Cytokine Production.

Chembiochem 2018 Jul 6;19(14):1476-1481. Epub 2018 Jun 6.

Institute for Glycomics, Griffith University, Gold Coast Campus, Parklands Drive, Southport, Queensland, 4215, Australia.

Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacterium and instigate intracellular signalling in the immune cell. There are structural similarities between the structures of TDM and phosphatidyl inositol mannoside (PIM). We thus hypothesized that these latter structures might also modulate an immune response in a similar manner. To test this, we synthesized a series of new mannose derivatives modified with fatty esters at the 6-position and assessed the release of inflammatory cytokines in human U937 macrophages under the induction of lipopolysaccharides (LPS) after glycolipid treatment. The results showed that the amount of two major cytokines-tumour necrosis factor (TNF)-α and interleukin (IL)-6-released from LPS-stimulated U937 cells decreased significantly when compared to a control upon treatment with the prepared glycolipids, thus indicating a reduction in cytokine production by the macrophages.
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http://dx.doi.org/10.1002/cbic.201800150DOI Listing
July 2018

Blocking IL-10 signalling at the time of immunization does not increase unwanted side effects in mice.

BMC Immunol 2017 08 15;18(1):40. Epub 2017 Aug 15.

School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast, QLD, 4333, Australia.

Background: Cancer therapeutic vaccine induced cytotoxic T cell (CTL) responses are pivotal for the killing of tumour cells. Blocking interleukin 10 (IL-10) signalling at the time of immunization increases vaccine induced CTL responses and improves prevention of tumour growth in animal models compared to immunization without an IL-10 signalling blockade. Therefore, this immunization strategy may have potential to curtail cancer in a clinical setting. However, IL-10 deficiency leads to autoimmune disease in the gut. Blocking IL-10 at the time of immunization may result in unwanted side effects, especially immune-pathological diseases in the intestine.

Methods: We investigated whether blocking IL-10 at the time of immunization results in intestinal inflammation responses in a mouse TC-1 tumour model and in a NOD autoimmune disease prone mouse model.

Results: We now show that blocking IL-10 at the time of immunization increases IL-10 production by CD4+ T cells in the spleen and draining lymph nodes, and does not result in blood cell infiltration to the intestines leading to intestinal pathological changes. Moreover, immunization with papillomavirus like particles combined with simultaneously blocking IL-10 signalling does not increase the incidence of autoimmune disease in Non-obese diabetic (NOD) mice.

Conclusions: Our results indicate that immunization with an IL-10 inhibitor may facilitate the generation of safe, effective therapeutic vaccines against chronic viral infection and cancer.
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http://dx.doi.org/10.1186/s12865-017-0224-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557397PMC
August 2017

Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10.

Hum Vaccin Immunother 2017 03 29;13(3):518-527. Epub 2016 Sep 29.

a Genecology Research Centre , University of the Sunshine Coast , Maroochydore , DC , Australia.

Interleukin 10 (IL-10) is a cytokine that is able to downregulate inflammation. Its overexpression is directly associated with the difficulty in the clearance of chronic viral infections, such as chronic hepatitis B, hepatitis C and HIV infection, and infection-related cancer. IL-10 signaling blockade has been proposed as a promising way of clearing chronic viral infection and preventing tumor growth in animal models. Recently, we have reported that peptides with a helical repeating pattern of hydrophobic and hydrophilic residues are able to inhibit IL-10 significantly both in vitro and in vivo. In this work, we seek to further study the inhibiting mechanism of these peptides using sequence-modified peptides. As evidenced by both experimental and molecular dynamics simulation in concert the N-terminal hydrophobic peptide constructed with repeating hydrophobic and hydrophilic pattern of residues is more likely to inhibit IL10. In addition, the sequence length and the ability of protonation are also important for inhibition activity.
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http://dx.doi.org/10.1080/21645515.2016.1238537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360125PMC
March 2017

Multi-constituent identification in Australian cane toad skin extracts using high-performance liquid chromatography high-resolution tandem mass spectrometry.

J Pharm Biomed Anal 2016 Sep 1;129:260-272. Epub 2016 Jul 1.

Institute for Glycomics and School of Medical Science, Gold Coast Campus, Griffith University, Australia. Electronic address:

Toad skins and venom glandular secretions have been widely used for centuries in traditional Chinese and Japanese medicine for the treatment of various ailments such as cancer, sores, toothache, local inflammation and pain. The active chemical constituents from traditional oriental medicines have demonstrated potential in the development of effective therapeutic pharmaceuticals. Our primary focus in this research was to identify and characterise 'active' compounds or groups of compounds for their potential as neuropsychiatric disorder therapeutics. For this aim, we utilised a variety of solvents, i.e., the aqueous, 60% ethanol (aqueous) and acetic acid (aq) (at two different pHs) for extractions of Australian cane toad skins to identify chemical constituents. The identification of compounds was carried out using HPLC-ESI-Q-TOF-MS/MS based on the accurate mass measurement for molecular ions and MS/MS analysis, whereby accurate mass pseudo-molecular ions and characteristic fragment ions were compared to published reference data, including mass bank and NIST. As a result, we have to date identified 42 major constituents including alkaloids, amino acids, bufadienolides, fatty acids, nucleobases, nucleosides and vitamins mostly from the aqueous and 60% ethanol extracts. Of the 42 constituents identified, 29 were found in the aqueous extract, 35 were found in the ethanol (aq) extract and only 10 in the pH 1.78 acetic acid extract and 11 in the pH 2.17 acetic acid extract of the cane toad skins. Therefore, the aqueous and 60% ethanolic extracts present the greatest potential for ongoing development in our assays. There have been no previous reports on the identification of many of the constituents we have here identified in Australian cane toad skins. These findings, while somewhat consistent with findings in toad skins in other countries, identifies the presence of potential bioactive constituents. Our results showed that HPLC-ESI-Q-TOF-MS/MS is an effective method to characterise and identify components in Australian cane toad skin extracts. Chemical profiling is an essential initial step in the identification and therapeutic exploitation of bioactive agents present in Australian cane toad skin extracts.
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http://dx.doi.org/10.1016/j.jpba.2016.06.031DOI Listing
September 2016

Cane Toad Skin Extract-Induced Upregulation and Increased Interaction of Serotonin 2A and D Receptors via G Signaling Pathway in CLU213 Cells.

J Cell Biochem 2017 05 5;118(5):979-993. Epub 2017 Jan 5.

School of Medical Science and Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.

Recent evidences show that activation of serotonin 2A receptors (5-HT R) by agonists is significant in improving therapeutic activity of disease conditions, such as obsessive-compulsive disorder (OCD). Though the exact molecular mechanism is still not well understood, it is thought to involve agonist-driven, enhanced expression of 5-HT R in certain areas of brain, such as the pre-frontal cortex (PFC). Several other reports have also demonstrated association of OCD with lower dopamine receptor (D R) availability, primarily in the striatum of the brain along with dysfunction of 5-HT R-D R heteromer regulation. We thus hypothesized that compound(s) interacting with this molecular mechanism could be developed as drugs for long-term beneficial effects against OCD. In the present study, we have obtained experimental evidence in cultured neuronal cells (CLU213) that aqueous extract (AE, 50 μg/mL, P < 0.05) of the Australian cane toad skin significantly increased the levels of 5-HT R and D R protein and mRNA expression. AE was also found to enhance the interaction between 5-HT R and D R and formation of expression of 5-HT R-D R heteromer using co-immunoprecipitation and Western blot. Further investigation showed the involvement of classical signaling pathway (G -PLCβ) along with c-FOS transcription factor preferentially in 5-HT -mediated agonist activation. These results obtained demonstrated that AE upregulates 5-HT R by a mechanism that appears to involve G -PLCβ signaling pathway and c-FOS transcription factor activation. We indicate this enhanced 5-HT R and D R expression and their interaction to induce increased 5-HT R-D R heteromer formation by exposure to AE might provide a molecular mechanism to develop potential novel drug candidates to ameliorate OCD symptoms. J. Cell. Biochem. 118: 979-993, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25627DOI Listing
May 2017

Aqueous and Ethanol Extracts of Australian Cane Toad Skins Suppress Pro-Inflammatory Cytokine Secretion in U937 Cells via NF-κB Signaling Pathway.

J Cell Biochem 2016 12 15;117(12):2769-2780. Epub 2016 Jun 15.

School of Medical Science and Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.

Toad skin extracts, such as aqueous extracts (AE) of Chinese toad skins, have demonstrated therapeutic benefits for a range of diseases including pain, inflammation, swelling, heart failure, and various types of cancers. In this study, we investigated the anti-inflammatory potential of an AE (0.1-10 μg/mL) and a 60% ethanol extract (EE; 0.1-10 μg/mL) from Australian cane toad (Bufo marinus) skins and the known bioactive compound, bufotenine (BT; 0.1-10 nM). The assay employed a model of the human monocyte cell line U937 stimulated with lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) for the release of tumor necrosis factor (TNF)-α and interleukin (IL)-6. We demonstrated that AE, EE, and BT significantly inhibited the release and expression of TNF-α and IL-6 in a dose-dependent manner when the cells were pre-treated at non-cytotoxic concentrations. Further investigation revealed that the inhibition of TNF-α and IL-6 release and expression was associated with the suppression of nuclear factor (NF)-kappa (κ)B activation. These results indicate that AE, EE, and BT are strong inflammation inhibitors, thus have the potential for further development as anti-inflammatory therapeutic agents from a natural source regarded as a feral pest in Australia. J. Cell. Biochem. 117: 2769-2780, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25577DOI Listing
December 2016

Investigation the Possibility of Using Peptides with a Helical Repeating Pattern of Hydro-Phobic and Hydrophilic Residues to Inhibit IL-10.

PLoS One 2016 21;11(4):e0153939. Epub 2016 Apr 21.

Genecology Research Centre, University of the Sunshine Coast, Maroochydore DC, Australia.

Blockade of IL-10 signalling clears chronic viral and bacterial infections. Immunization together with blockade of IL-10 signalling or relatively low level of IL-10 further enhances viral and bacterial clearance. IL-10 functions through binding to interleukin 10 receptor (IL-10R). Here we showed that peptides P1 and P2 with the hydrophobic and hydrophilic pattern of the IL10R-binding helix in IL-10 could bind with either IL-10R1 or IL-10, and inhibit inflammatory signals with long duration and negligible cytotoxicity in vitro. Furthermore, P2 can enhance antigen specific CD8+ T cell responses in mice induced by the vaccine based on a long peptide of protein E7 in a human papillomavirus type 16.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839630PMC
September 2016

Genomic and immunologic factors associated with viral pathogenesis in a lethal EV71 infected neonatal mouse model.

Mol Med Rep 2016 May 31;13(5):4183-90. Epub 2016 Mar 31.

Key Laboratory of Rare and Uncommon Diseases, Department of Microbiology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062, P.R. China.

Hand, foot and mouth disease (HFMD) caused by enterovirus 71 (EV71) has emerged as a major health problem in China and worldwide. The present study aimed to understand the virological features of EV71 and host responses resulting from EV71 infection. Six different EV71 strains were isolated from HFMD patients with severe or mild clinical symptoms, and were analyzed for pathogenicity in vitro and in vivo. The results demonstrated that the six virus strains exhibited similar cytopathogenic effects on susceptible MA104 cells. However, marked differences in histological and immunopathological changes were observed when mice were inoculated with the different virus strains. Thus, the viruses studied were divided into two groups, highly or weakly pathogenic. Two representative virus strains, JN200804 and JN200803 (highly and weakly pathogenic, respectively) were studied further to investigate pathogenicity-associated factors, including genetic mutations and immunopathogenesis. The present study has demonstrated that highly pathogenic strains have stable genome and amino acid sequences. Notably, the present study demonstrated that a highly pathogenic strain induced a significant increase of the bulk CD4 T cell levels at 3 days post‑inoculation. In conclusion, the current study demonstrates that genomic and immunologic factors may be responsible for the multiple tissue damage caused by highly pathogenic EV71 infection.
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http://dx.doi.org/10.3892/mmr.2016.5080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838153PMC
May 2016

The yield and quality of cellular and bacterial DNA extracts from human oral rinse samples are variably affected by the cell lysis methodology.

J Microbiol Methods 2016 Mar 23;122:64-72. Epub 2016 Jan 23.

School of Medical Science, Menzies Health Institute Queensland, Griffith University, Gold Coast 4215, Australia. Electronic address:

Recent culture-independent studies have enabled detailed mapping of human microbiome that has not been hitherto achievable by culture-based methods. DNA extraction is a key element of bacterial culture-independent studies that critically impacts on the outcome of the detected microbial profile. Despite the variations in DNA extraction methods described in the literature, no standardized technique is available for the purpose of microbiome profiling. Hence, standardization of DNA extraction methods is urgently needed to yield comparable data from different studies. We examined the effect of eight different cell lysis protocols on the yield and quality of the extracted DNA from oral rinse samples. These samples were exposed to cell lysis techniques based on enzymatic, mechanical, and a combination of enzymatic-mechanical methods. The outcome measures evaluated were total bacterial population, Firmicutes levels and human DNA contamination (in terms of surrogate GAPDH levels). We noted that all three parameters were significantly affected by the method of cell lysis employed. Although the highest yield of gDNA was obtained using lysozyme-achromopeptidase method, the lysozyme-zirconium beads method yielded the peak quantity of total bacterial DNA and Firmicutes with a lower degree of GAPDH contamination compared with the other methods. Taken together our data clearly points to an urgent need for a consensus, standardized DNA extraction technique to evaluate the oral microbiome using oral rinse samples. Further, if Firmicutes levels are the focus of investigation in oral rinse microbiome analyses then the lysozyme-zirconium bead method would be the method of choice in preference to others.
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http://dx.doi.org/10.1016/j.mimet.2016.01.013DOI Listing
March 2016

EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model.

Theranostics 2015 20;5(12):1456-72. Epub 2015 Oct 20.

2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.

Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.
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http://dx.doi.org/10.7150/thno.11692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672025PMC
August 2016

Prion protein scrapie and the normal cellular prion protein.

Prion 2016 ;10(1):63-82

a Division of Molecular and Gene Therapies, Menzies Health Institute, Griffith University , Gold Coast , QLD , Australia.

Prions are infectious proteins and over the past few decades, some prions have become renowned for their causative role in several neurodegenerative diseases in animals and humans. Since their discovery, the mechanisms and mode of transmission and molecular structure of prions have begun to be established. There is, however, still much to be elucidated about prion diseases, including the development of potential therapeutic strategies for treatment. The significance of prion disease is discussed here, including the categories of human and animal prion diseases, disease transmission, disease progression and the development of symptoms and potential future strategies for treatment. Furthermore, the structure and function of the normal cellular prion protein (PrP(C)) and its importance in not only in prion disease development, but also in diseases such as cancer and Alzheimer's disease will also be discussed.
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http://dx.doi.org/10.1080/19336896.2015.1110293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981215PMC
January 2017

Combining anaerobic bacterial oncolysis with vaccination that blocks interleukin-10 signaling may achieve better outcomes for late stage cancer management.

Hum Vaccin Immunother 2016 03;12(3):599-606

a School of Medical Science and Griffith Health Institute, Griffith University , Gold Coast , QLD , Australia.

Late stage solid tumors cause significant cancer mortality rates worldwide and effective therapy remains a big challenge. Cancer therapeutic vaccines elicit tumor specific T cells that kill tumor cells yet often fail to result in tumor destruction because of the limited T cell response and the local immune-suppressive environment. Blocking interleukin 10 (IL-10) signaling at the time of therapeutic vaccination elicits much stronger T cell responses than vaccination without IL-10 blocking. Anaerobic oncolytic bacteria target hypoxic regions of the late stage tumor tissues which not only stops tumor growth but also provides a pro-inflammatory environment that may increase the effectiveness of a therapeutic vaccine by recruiting more effector T cells to tumor site. In this review, we argue that combining both bacterial and vaccine therapies may improve the efficiency of late stage cancer management.
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http://dx.doi.org/10.1080/21645515.2015.1089008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964640PMC
March 2016

Indolealkylamines from Toad Vertebrates and Sea Invertebrates - Their Identification and Potential Activities on the Central Nervous System.

Cent Nerv Syst Agents Med Chem 2016 ;16(3):197-207

School of Medical Science & Menzies Health Institute Queensland, Gold Coast campus, Griffith University, Southport, Qld, 4222 Australia.

Indolealkylamines (IAAs) are biogenic amines and derivatives of 5-hydroxytryptamine, acting primarily on serotonin receptors. IAAs are often considered the most thoroughly investigated group of aromatic amines in the amphibian skin. On the contrary, at present the detailed knowledge of these compounds in lower organisms is still limited and the biogenic amine receptors, mediating hormonal and modulatory functions, are largely unknown in primitive invertebrates. However, some active research is currently underway investigating this class of biogenic amines. Notably, during the last three decades several investigations have demonstrated the biological activity of endogenous biogenic amines in cnidarians, which are known to be the lowest beings equipped with an effective, even though rudimentary, nervous system. Toads, especially those from the Bufonidae family, constitute a significant part of the amphibian family and are an identified source of IAAs. To date fourteen IAAs have been identified in the skins of toad species. All are 5-substituted IAA derivatives acting mainly on the central nervous system (CNS), with most exhibiting some degrees of 5-HT2A receptor selectivity. This selective ability presents potential for their use in the development of treatments for various disorders such as schizophrenia, depression, anxiety, obsessive-compulsive disorders and chronic pain conditions. There are indications that some IAAs may also show subclass selectivity through binding to multiple 5-HT receptor subtypes. Thus, there exists an additional promising platform for the development of therapeutics targeting multiple 5-HT receptors. In this review, IAAs occurring naturally in various species of toad skins, which have been identified and isolated since 1944 are summarized and comparisons are made with similar biogenic amines recognized in cnidarians to date. Such comparisons highlight the potential to utilize existing knowledge gathered from vertebrates, such as toads in order to improve the understanding of the activities of such compounds in lower invertebrates.
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http://dx.doi.org/10.2174/1871524915666150724100245DOI Listing
February 2017

Chansu inhibits the expression of cortactin in colon cancer cell lines in vitro and in vivo.

BMC Complement Altern Med 2015 Jul 2;15:207. Epub 2015 Jul 2.

Menzies Health Institute, Queensland and School of Medical Science, Griffith University, Gold Coast, 4222, QLD, Australia.

Background: Chansu is a transitional Chinese medicine that has been used for centuries as therapy for inflammation, anaesthesia and arrhythmia in China and other Asian countries. Recently, it has also been used for anti-cancer purposes. We have previously shown that Chansu has a huge pro-apoptotic potential on colon cancer cells, but to date the detailed mechanism of this action is not well understood.

Methods: One of the major components of Chansu, Cinobufagin (CBF) was used to treat cancer cells. The expressions of levels of cortactin, an important factor in tumour progression and cancer invasion, were assessed in in vitro and in vivo experiments. Additional analyses were performed in subcellular protein fractions and immune-fluorescent staining was used to define cortactin protein expression and the changes of location in CBF-treated cells.

Results: CBF strongly inhibited the expression of cortactin in HCT116 cells. There were reductions of both mRNA transcription and protein synthesis, which were more significant in the absence of oxygen in vitro. In addition, nuclear translocation of cortactin was observed in HCT116 cells post CBF exposure but not in the negative control, indicating that CBF is likely to interrupt co-localisation of cortactin to cytoskeletal proteins. Most importantly, CBF could diminish the expression of cortactin in human HCT116 xenograft tumours in nude mouse in vivo.

Conclusions: CBF inhibits cortactin expression and nuclear translocation in colon cancer cells in vitro and in mouse models bearing human colon tumour in vivo, suggesting it might disrupt actin-regulated cell movement. Thus, CBF or Chansu could be developed as an effective anti-cancer therapy to stop local invasion and metastasis.
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http://dx.doi.org/10.1186/s12906-015-0723-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489352PMC
July 2015
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