Thermal therapy induced fluid pressure and stress reductions in a solid tumor.

This paper presents an investigation on the interstitial fluid pressure and stress reductions in a vascularized solid tumor using a thermal therapy approach. The solid tumor is modeled as a fluid infiltrated poroelastic medium with a pressure source subjected to spatial heating. The distributions of temperature, interstitial fluid pressure, strains and stresses in a spherical tumor are obtained using a thermoporoelasticity theory in which the extracellular solid matrix and the interstitial fluid have different coefficient of thermal expansion (CTE). The numerical results for a solid tumor subjected to uniform spatial heating indicate that the CTE of the solid matrix of the tumor plays a crucial role in the reductions in the fluid pressure and effective stresses caused by the thermal therapy. The pore pressure and effective stresses are reduced when the CTE of the solid matrix is higher than that of the interstitial fluid. The reductions in fluid pressure and stresses may become significant depending on the difference between the CTEs of the solid matrix and interstitial fluid. The reductions reach the maximum at the tumor center and decrease with increasing radial distance from the tumor center. Finally, the thermally induced fluid flow is directed from the surface towards the center thereby potentially improving the microcirculation in the solid tumor.

Microbiome Crosstalk in Immunotherapy and Antiangiogenesis Therapy.

The human body and its microbiome constitute a highly delicate system. The gut microbiome participates in the absorption of the host's nutrients and metabolism, maintains the microcirculation, and modulates the immune response. Increasing evidence shows that gut microbiome dysbiosis in the body not only affects the occurrence and development of tumors but also tumor prognosis and treatment. Microbiome have been implicated in tumor control in patients undergoing anti- angiogenesis therapy and immunotherapy. In cases with unsatisfactory responses to chemotherapy, radiotherapy, and targeted therapy, appropriate adjustment of microbes abundance is considered to enhance the treatment response. Here, we review the current research progress in cancer immunotherapy and anti- angiogenesis therapy, as well as the unlimited potential of their combination, especially focusing on how the interaction between intestinal microbiota and the immune system affects cancer pathogenesis and treatment. In addition, we discuss the effects of microbiota on anti-cancer immune response and anti- angiogenesis therapy, and the potential value of these interactions in promoting further research in this field.

Tumor radiosensitization by photobiomodulation.

PURPOSE: To investigate the safety of photobiomodulation therapy (PBM) in tumors and its potential as a radiosensitizer when combined with radiotherapy. METHODS: We have performed in vitro experiments in A431 cells to assess proliferation and cell cycle after PBM, as well as clonogenic assay and H2AX-gamma immunolabeling to quantify double strand breaks after the combination of PBM and radiation. In vivo experiments in xenografts included Kaplan-Meier survival analysis, optical coherence tomography (OCT) and histological analysis. RESULTS: PBM did not induce proliferation in vitro, but increased the G2/M fraction by 27% 24h after illumination, resulting in an enhancement of 30% in radiation effect in the clonogenic assay. The median survival of the PBM-RT group increased by 4 days and the hazard ratio was 0.417 (CI 95%: 0.173-1.006) when compared to radiation alone. OCT analysis over time demonstrated that PBM increases tumor necrosis due to radiation, and histological analysis showed that illumination increased cell differentiation and angiogenesis, which may play a role in the synergetic effect of PBM and radiation. CONCLUSION: PBM technique may be one of the most appropriate approaches for radiosensitizing tumors while protecting normal tissue because of its low cost and low training requirements for staff.

Arctigenin, an anti-tumor agent; a cutting-edge topic and up-to-the-minute approach in cancer treatment.

Today, herbal-derived compounds are being increasingly studied in cancer treatment. Over the past decade, Arctigenin has been introduced as a bioactive dibenzylbutyrolactone lignan which is found in Chinese herbal medicines. In addition to anti-microbial, anti-inflammatory, immune-modulatory functions, Arctigenin has attracted growing attention due to its anti-tumor capabilities. It has been shown that Arctigenin can induce apoptosis and necrosis and abolish drug resistance in tumor cells by inducing apoptotic signaling pathways, caspases, cell cycle arrest, and the modulating proteasome. Moreover, Arctigenin mediates other anti-tumor functions through several mechanisms. It has been demonstrated that Arctigenin can act as an anti-inflammatory compound to inhibit inflammation in the tumor microenvironment. It also downregulates factors involved in tumor metastasis and angiogenesis, such as matrix metalloproteinases, N-cadherin, TGF-ß, and VEGF. Additionally, Arctigenin, through modulation of MAPK signaling pathways and stress-related proteins, is able to abolish tumor cell growth in nutrient-deprived conditions. Due to the limited solubility of Arctigenin in water, it is suggested that modification of this compound through amino acid esterification can improve its pharmacogenetic properties. Collectively, it is hoped that using Arctigenin or its derivates might introduce new chemotherapeutic approaches in future treatment.

Evaluation of antiangiogenic and antiproliferative potential of ethanolic extracts of Andrographis echioides using in vitro and in ovo assays.

INTRODUCTION: Andrographis echioides is a prevalently used medicinal herb in South Asian countries. Scientific researches with the extracts of A. echioides revealed its antipyretic, anti-inflammatory, antimicrobial, ulceroprotective, and hepatoprotective properties. This study was done to elucidate antiproliferative and antiangiogenic potential of ethanolic extracts of A. echioides (EEAE) by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and chorioallantoic membrane (CAM) assay. MATERIALS AND METHODS: EEAE was prepared using Soxhlet apparatus with ethanol after being sun-dried and powdered. MCF 7 (human invasive breast ductal carcinoma) cell lines retaining attributes of differentiated mammary epithelium with both estrogen and progesterone receptors were treated with EEAE, and antiproliferative effect was seen using Mosmann method of MTT assay using 5-fluorouracil (5-FU) as a comparator. The evaluation of antiangiogenic potential of EEAE was done by comparing mean vessel density (MVD) in chick CAM after treatment with EEAE, thalidomide, and vascular endothelial growth factor (VEGF) using CAM assay, an in ovo assay. RESULTS: EEAE displayed antiproliferative activity from low to high concentrations with MTT assay. The IC50 of EEAE and 5-FU was 62.5 and 15.6 µg/ml, respectively (P < 0.05). The exhibition of its antiangiogenic activity increased proportionately with increasing concentration. VEGF increased MVD by 45.94%; thalidomide decreased it by 53.76%. There was a decrease of MVD by 5.91%, 20.46%, and 35.95% at concentrations of 25, 50, and 100 µg of EEAE, respectively. CONCLUSION: EEAE possessed significant antiangiogenic and antiproliferative activity, making them a promising substrate in the development of a novel anticancer drug and can be successfully used in the therapy of various cancers after establishment of the anticancer effects in animal models and subsequently in clinical trials.

The Discovery of Naringenin as Endolysosomal Two-Pore Channel Inhibitor and Its Emerging Role in SARS-CoV-2 Infection.

The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19.

Insights into the antitumor mechanism of ginsenosides Rg3.

Panax ginseng, an ancient herb, belonging to Chinese traditional medicine, is an important herb that has a remarkable impact on various diseases. Ginsenoside Rg3, one of the most abundant ginsenosides, exerts significant functions in the prevention of various types of cancers with few side effects. In the present review, its functional molecular mechanisms are explored, including the improvement of antioxidant and anti-inflammation properties, immune regulation, induction of tumor apoptosis, prevention of tumor invasion and metastasis, tumor proliferation and angiogenesis, and reduction of chemoresistance and radioresistance. On the other hand, metabolism, pharmacokinetics and clinical indications of Rg3 are also discussed. The biological functional role of ginsenoside Rg3 may be associated with that it is a steroid glycoside with diverse biological activities and many signaling pathway can be regulated. Many clinical trials are highly needed to confirm the functions of ginsenoside Rg3.

An Insight into the Anti-Angiogenic and Anti-Metastatic Effects of Oridonin: Current Knowledge and Future Potential.

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients' outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin's anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action.

Antiangiogenic activity of zinc and zinc-sorafenib combination using the chick chorioallantoic membrane assay: A descriptive study.

AIM: Zinc, a trace element, is known for downregulating several proangiogenic growth factors and cytokines. However, its antiangiogenic activity is not adequately studied. The present study was aimed to evaluate the possible antiangiogenic activity of zinc via the chick chorioallantoic membrane (CAM) assay. Furthermore, the antiangiogenic activity of the combination therapy of zinc with various doses of sorafenib, a tyrosine kinase inhibitor, was evaluated. MATERIALS AND METHODS: A pilot study was initially conducted so as to select suitable doses of zinc and sorafenib. The antiangiogenic activity after combining zinc 2.5 µg/embryo with sorafenib 1 and 2 µg/embryo was also evaluated. The antiangiogenic activity was quantified in terms of total length of blood vessels, number of junctions, number of branching points, and mean length of the blood vessels. RESULTS: Zinc 2.5 µg/embryo showed significant (P < 0.05) antiangiogenic activity, as compared to the control group. However, its effect was not comparable to that of sorafenib 2 µg/embryo. The combination of zinc 2.5 µg/embryo with sorafenib 2 µg/embryo did not show an additive/synergistic effect. The combination of zinc 2.5 µg/embryo with sorafenib 1 µg/embryo produced an antiangiogenic activity which was comparable (P > 0.05) to that of sorafenib 2 µg/embryo. CONCLUSION: Zinc caused significant antiangiogenic activity in the CAM assay. The lack of addition/synergism in the zinc-sorafenib combination could have been due to the variability in the dose/ratio selection. Addition of zinc to sorafenib therapy could improve treatment tolerability, reduce cost of therapy, and reduce the emergence of drug resistance. Future mechanistic studies could identify the exact pharmacodynamics of zinc as an angiogenesis inhibitor.

Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis.

Alternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.

Clinical effects of curcumin in enhancing cancer therapy: A systematic review.

BACKGROUND: Curcumin is herbal compound that has been shown to have anti-cancer effects in pre-clinical and clinical studies. The anti-cancer effects of curcumin include inhibiting the carcinogenesis, inhibiting angiogenesis, and inhibiting tumour growth. This study aims to determine the Clinical effects of curcumin in different types of cancers using systematic review approach. METHODS: A systematic review methodology is adopted for undertaking detailed analysis of the effects of curcumin in cancer therapy. The results presented in this paper is an outcome of extracting the findings of the studies selected from the articles published in international databases including SID, MagIran, IranMedex, IranDoc, Google Scholar, ScienceDirect, Scopus, PubMed and Web of Science (ISI). These databases were thoroughly searched, and the relevant publications were selected based on the plausible keywords, in accordance with the study aims, as follows: prevalence, curcumin, clinical features, cancer. RESULTS: The results are derived based on several clinical studies on curcumin consumption with chemotherapy drugs, highlighting that curcumin increases the effectiveness of chemotherapy and radiotherapy which results in improving patient's survival time, and increasing the expression of anti-metastatic proteins along with reducing their side effects. CONCLUSION: The comprehensive systematic review presented in this paper confirms that curcumin reduces the side effects of chemotherapy or radiotherapy, resulting in improving patients' quality of life. A number of studies reported that, curcumin has increased patient survival time and decreased tumor markers' level.

Mechanistic investigations of antitumor activity of a Rhodamine B­oleanolic acid derivative bioconjugate.

Cancer remains a major health problem worldwide due to its high mortality rate. New therapeutic options highlight the importance of discovering new compounds that target the tumor microenvironment, interrupt angiogenesis and act selectively. The present study assessed the antitumor effect and investigated the mechanism of action of a rhodamine B­conjugated oleanolic acid derivative (RhodOA). Consequently, the compound was tested on different human tumor cell lines (A375 melanoma, A549 lung adenocarcinoma and MDA­MB­231 breast adenocarcinoma) and on a non­tumor cell line HaCaT human keratinocyte. RhodOA produced a dose­dependent decrease in tumor cell viability especially in the melanoma cells while affecting the keratinocytes less. In melanoma cells, RhodOA reduced cell migration and produced condensation of cell nuclei and of actin fibers. Furthermore, an impairment in melanoma cell mitochondrial function was observed, while the mitochondrial function of keratinocytes was left intact. In the in ovo chorioallantoic membrane model, RhodOA elicited antiangiogenic effect, without showing irritation effect on the membrane. The study provides information on the selective antitumor effect of the derivative and its ability to inhibit cellular respiration, therefore RhodOA can be classified as 'MITOCAN'.

Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy.

Hyperthermia has demonstrated clinical success in improving the efficacy of both chemo- and radio-therapy in solid tumors. Pre-clinical and clinical research studies have demonstrated that targeted hyperthermia can increase tumor blood flow and increase the perfused fraction of the tumor in a temperature and time dependent manner. Changes in tumor blood circulation can produce significant physiological changes including enhanced vascular permeability, increased oxygenation, decreased interstitial fluid pressure, and reestablishment of normal physiological pH conditions. These alterations in tumor physiology can positively impact both small molecule and nanomedicine chemotherapy accumulation and distribution within the tumor, as well as the fraction of the tumor susceptible to radiation therapy. Hyperthermia can trigger drug release from thermosensitive formulations and further improve the accumulation, distribution, and efficacy of chemotherapy.

Antitumor, Anti-Inflammatory and Antiallergic Effects of Agaricus blazei Mushroom Extract and the Related Medicinal Basidiomycetes Mushrooms, Hericium erinaceus and Grifola frondosa: A Review of Preclinical and Clinical Studies.

Since the 1980s, medicinal effects have been documented in scientific studies with the related Basidiomycota mushrooms Agaricus blazei Murill (AbM), Hericium erinaceus (HE) and Grifola frondosa (GF) from Brazilian and Eastern traditional medicine. Special focus has been on their antitumor effects, but the mushrooms' anti-inflammatory and antiallergic properties have also been investigated. The antitumor mechanisms were either direct tumor attack, e.g., apoptosis and metastatic suppression, or indirect defense, e.g., inhibited tumor neovascularization and T helper cell (Th) 1 immune response. The anti-inflammatory mechanisms were a reduction in proinflammatory cytokines, oxidative stress and changed gut microbiota, and the antiallergic mechanism was amelioration of a skewed Th1/Th2 balance. Since a predominant Th2 milieu is also found in cancer, which quite often is caused by a local chronic inflammation, the three conditions-tumor, inflammation and allergy-seem to be linked. Further mechanisms for HE were increased nerve and beneficial gut microbiota growth, and oxidative stress regulation. The medicinal mushrooms AbM, HE and GF appear to be safe, and can, in fact, increase longevity in animal models, possibly due to reduced tumorigenesis and oxidation. This article reviews preclinical and clinical findings with these mushrooms and the mechanisms behind them.

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process.

Chemotherapeutics are sometimes administered with drugs, like antiangiogenic compounds, to increase their effectiveness. Melatonin exerts antitumoral actions through antiangiogenic actions. We studied if melatonin regulates the response of HUVECs to chemotherapeutics (docetaxel and vinorelbine). The inhibition that these agents exert on some of the processes involved in angiogenesis, such as, cell proliferation, migratory capacity or vessel formation, was enhanced by melatonin. Regarding to estrogen biosynthesis, melatonin impeded the negative effect of vinorelbine, by decreasing the activity and expression of aromatase and sulfatase. Docetaxel and vinorelbine increased the expression of VEGF-A, VEGF-B, VEGF-C, VEGFR-1, VEGFR-3, ANG1 and/or ANG-2 and melatonin inhibited these actions. Besides, melatonin prevented the positive actions that docetaxel exerts on the expression of other factors related to angiogenesis like JAG1, ANPEP, IGF-1, CXCL6, AKT1, ERK1, ERK2, MMP14 and NOS3 and neutralized the stimulating actions of vinorelbine on the expression of FIGF, FGFR3, CXCL6, CCL2, ERK1, ERK2, AKT1, NOS3 and MMP14. In CAM assay melatonin inhibited new vascularization in combination with chemotherapeutics. Melatonin further enhanced the chemotherapeutics-induced inhibition of p-AKT and p-ERK and neutralized the chemotherapeutics-caused stimulatory effect on HUVECs permeability by modifying the distribution of VE cadherin. Our results confirm that melatonin blocks proangiogenic and potentiates antiangiogenic effects induced by docetaxel and vinorelbine enhancing their antitumor effectiveness.

Hyperthermia and smart drug delivery systems for solid tumor therapy.

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.

Targeting vasculogenic mimicry by phytochemicals: A potential opportunity for cancer therapy.

Vasculogenic mimicry (VM) is regarded as a process where very aggressive cancer cells generate vascular-like patterns without the presence of endothelial cells. It is considered as the main mark of malignant cancer and has pivotal role in cancer metastasis and progression in various types of cancers. On the other hand, resistance to the antiangiogenesis therapies leads to the cancer recurrence. Therefore, development of novel chemotherapies and their combinations is urgently needed for abolition of VM structures and also for better tumor therapy. Hence, identifying compounds that target VM structures might be superior therapeutic factors for cancers treatment and controlling the recurrence and metastasis. In recent times, naturally occurring compounds, especially phytochemicals have obtained great attention due to their safe properties. Phytochemicals are also capable of targeting VM structure and also their main signaling pathways. Consequently, in this review article, we illustrated key signaling pathways in VM, and the phytochemicals that affect these structures including curcumin, genistein, lycorine, luteolin, columbamine, triptolide, Paris polyphylla, dehydroeffusol, jatrorrhizine hydrochloride, grape seed proanthocyanidins, resveratrol, isoxanthohumol, dehydrocurvularine, galiellalactone, oxacyclododecindione, brucine, honokiol, ginsenoside Rg3, and norcantharidin. The recognition of these phytochemicals and their safety profile may lead to new therapeutic agents' development for VM elimination in different types of tumors.

Beyond Angiogenesis: Exploiting Angiocrine Factors to Restrict Tumor Progression and Metastasis.

Looking beyond tumor angiogenesis, the past decade has witnessed a fundamental change of paradigm with the discovery that the vascular endothelium does not just respond to exogenous cytokines, but exerts active "angiocrine" gatekeeper roles, controlling their microenvironment in an instructive manner. While vascular niches host disseminated cancer cells and promote their stemness, endothelial cell-derived angiocrine signals orchestrate a favorable immune milieu to facilitate metastatic growth. Here, we discuss recent advances in the field of tumor microenvironment research and propose angiocrine signals as promising targets of future mechanism-driven antimetastatic therapies, which may prove useful to synergistically combine with chemotherapy and immunotherapy.

Mathematical model to verify the role of magnetic field on blood flow and its impact on thermal behavior of biological tissue for tumor treatment.

The numerical computation has been performed to study the effects of static magnetic field on thermal behavior of tumor surrounded by living biological tissues and blood vessels. A small rectangular shaped tumor enclosing the blood vessel surrounded by healthy tissue is considered. The model consists of two-layer composite system in which the microvessel for blood flow is considered as a fluid layer and the living biological tissue including tumor as a solid layer. The wave bioheat transfer equation in the tissue layer together with energy transport equation for blood flow layer has been used in the cylindrical polar coordinates. The analytical expression for blood velocity in the presence of magnetic field has been used from Gold's solution. The computational work has been performed by employing the Crank-Nicolson finite difference method. A comparison has been made to validate our numerical results with the previous solution by setting some parameters. The temperature profiles have been plotted at different locations of the axial tissue length for various values of the Hartmann number, Prandtl number, Womersley number and Reynolds number. It is observed that the application of magnetic field increases heat transfer rate within tumor tissues which in turn attribute to an enhancement of temperature about 316 K or above for hyperthermic treatment in cancer therapy.

Numerical analysis of power dissipation requirement in magnetic hyperthermia problems.

Control of the therapeutic temperature is essential in performing magnetic fluid hyperthermia. Thus, reliable predictions of the power dissipation are required to determine the correct dosage of magnetic particles to be injected into the cancerous tissue prior to treatment. To meet this requirement, the present study evaluates the power dissipation requirement for two magnetic hyperthermia problems reported in the literature. There is a significant challenge for solving the bio-heat transfer model for concentric bi-layered solid spheres. Consequently, the present study employs a hybrid technique based on Laplace transformation and a modified discretization scheme to solve the considered hyperthermia problems. Analytical solutions are provided to demonstrate the validity of the proposed approach. The unreliability of the results presented in the literature is then demonstrated using the proposed numerical scheme. In general, the results presented in this study show that the power dissipation required to maintain an effective temperature range in the tumor domain is related to the rate of temperature rise, the tumor size, the blood perfusion rate, and the tissue properties. In particular, the power dissipation should be increased for the cooling effect of blood perfusion or a smaller tumor volume.