Multi-Faceted Role of Luteolin in Cancer Metastasis: EMT, Angiogenesis, ECM Degradation and Apoptosis.

Luteolin (3',4',5,7-tetrahydroxyflavone), a member of the flavonoid family derived from plants and fruits, shows a wide range of biomedical applications. In fact, due to its anti-inflammatory, antioxidant and immunomodulatory activities, Asian medicine has been using luteolin for centuries to treat several human diseases, including arthritis, rheumatism, hypertension, neurodegenerative disorders and various infections. Of note, luteolin displays many anti-cancer/anti-metastatic properties. Thus, the purpose of this review consists in highlighting the relevant mechanisms by which luteolin inhibits tumor progression in metastasis, i.e., affecting epithelial-mesenchymal transition (EMT), repressing angiogenesis and lysis of extracellular matrix (ECM), as well as inducing apoptosis.

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer.

Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of life, with consequent additional social costs. In recent decades, several studies explored the role of agents acting within the bone microenvironment to counteract BM development, and several bone-targeting agents (BTAs) have been introduced in the clinical practice to manage bone lesions and reduce the risk of skeletal complications. However, long-term exposure to these agents is not free from potential toxicities and needs careful monitoring. In this context, the potential capability to prevent BM onset in selected BC patients, through the early administration of BTAs, has been explored by several researchers, with the belief that "prevention is better than cure" and that, ultimately, metastatic BC is an incurable condition. Here, we revised the mechanisms of BM development in BC as well as the strategies for selecting high-risk patients suitable for early BTA treatment.

The unique pharmacological characteristics of mifepristone (RU486): from terminating pregnancy to preventing cancer metastasis.

Mifepristone (RU486) is a born-for-woman molecule discovered three decades ago. Unlike those antihypertensive and antipsychotic pharmaceutical blockbusters, this abortifacient offers relatively low profit potential. Current understanding of mechanism of action of mifepristone and its on-going clinical trials are changing our views on the drug beyond its abortifacient scope. Here we briefly review its metabolism and pharmacokinetic properties including its unique enterohepatic circulation, its mechanisms of actions involving antiprogesterone and antiglucocorticoid, growth inhibition of various cancer cell lines, suppression of invasive and metastatic cancer potential, downregulation of Cdk2, Bcl-2, and NF-kappa B, interference of heterotypic cell adhesion to basement membrane, and cell migration. We comprehensively analyze recent results from preclinical and clinical studies using mifepristone as an anticancer drug for breast, meningioma, and gliomas tumors in the central nervous system, prostate cancer, ovarian and endometrial cancer, and gastric adenocarcinoma. Although mifepristone has more benefits for global public health than we originally thought, its effect as a postmetastatic chemotherapeutic agent is limited. Nonetheless, owing to its unique safe, metabolism and other pharmacological properties, metapristone (the primary metabolite of mifepristone) may have potential for cancer metastatic chemoprevention.

Fuyuan decoction prevents nasopharyngeal carcinoma metastasis by inhibiting circulating tumor cells/ endothelial cells interplay and enhancing anti-cancer immune response.

Distant metastasis is a major cause of treatment failure in cancer patients and a key challenge to improving cancer care today. We hypothesized that enhancing anti-cancer immune response and inhibiting circulating tumor cells (CTCs) adhesion and transendothelial migration through synergistic multi-target approaches may effectively prevent cancer metastasis. "Fuyuan Decoction" (FYD) is a traditional Chinese medicine compound that is widely used to prevent postoperative metastasis in cancer patients, but its underlying mechanism remains unclear. In this work, we systematically elucidated the underlying molecular mechanism by which FYD prevents cancer metastasis through multi-compound and multi-target synergies in vitro and in vivo. FYD significantly prevented cancer metastasis at non-cytotoxic concentrations by suppressing the adhesion of CTCs to endothelial cells and their subsequent transendothelial migration, as well as enhancing anti-cancer immune response. Mechanistically, FYD interrupts adhesion of CTCs to vascular endothelium by inhibiting TNF-α-induced CAMs expression via regulation of the NF-κB signaling pathway in endothelial cells. FYD inhibits invasion and migration of CTCs by suppressing EMT, PI3K/AKT and FAK signaling pathways. Moreover, FYD enhances the anti-cancer immune response by significantly increasing the population of Tc and NK cells in the peripheral immune system. In addition, the chemical composition of FYD was determined by UPLC-HRMS, and the results indicated that multiple compounds in FYD prevents cancer metastasis through multi-target synergistic treatment. This study provides a modern medical basis for the application of FYD in the prevention of cancer metastasis, and suggesting that multi-drug and multi-target synergistic therapy may be one of the most effective ways to prevent cancer metastasis.

Metastasis prevention: How to catch metastatic seeds.

Despite considerable advances in the evolution of anticancer therapies, metastasis still remains the main cause of cancer mortality. Therefore, current strategies for cancer cure should be redirected towards prevention of metastasis. Targeting metastatic pathways represents a promising therapeutic opportunity aimed at obstructing tumor cell dissemination and metastatic colonization. In this review, we focus on preclinical studies and clinical trials over the last five years that showed high efficacy in suppressing metastasis through targeting lymph node dissemination, tumor cell extravasation, reactive oxygen species, pre-metastatic niche, exosome machinery, and dormancy.

Sensitization of Resistant Cells with a BET Bromodomain Inhibitor in a Cell Culture Model of Deep Intrinsic Resistance in Breast Cancer.

We treated highly metabolically adaptable (SUM149-MA) triple-negative inflammatory breast cancer cells and their control parental SUM149-Luc cell line with JQ1 for long periods to determine its efficacy at inhibiting therapy-resistant cells. After 20 days of treatment with 1-2 µM of JQ1, which killed majority of cells in the parental cell line, a large number of SUM149-MA cells survived, consistent with their pan-resistant nature. Interestingly, though, the JQ1 treatment sensitized resistant cancer cells in both the SUM149-MA and SUM149-Luc cell lines to subsequent treatment with doxorubicin and paclitaxel. To measure JQ1-mediated sensitization of resistant cancer cells, we first eradicated approximately 99% of relatively chemotherapy-sensitive cancer cells in culture dishes by long treatments with doxorubicin or paclitaxel, and then analyzed the remaining resistant cells for survival and growth into colonies. In addition, combination, rather than sequential, treatment with JQ1 and doxorubicin was also effective in overcoming resistance. Notably, Western blotting showed that JQ1-treated cancer cells had significantly lower levels of PD-L1 protein than did untreated cells, indicating that JQ1 treatment may reduce tumor-mediated immune suppression and improve the response to immunotherapy targeting PD-L1. Finally, JQ1 treatment with a low 62.5 nM dose sensitized another resistant cell line, FC-IBC02-MA, to treatment with doxorubicin and paclitaxel.

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice.

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients.

Sensitization of Resistant Breast Cancer Cells with a Jumonji Family Histone Demethylase Inhibitor.

In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in a breast cancer model. The model was based on a function-based approach to the selection of cancer cells in a cell culture that can survive a variety of challenges in prolonged, but reversible, quiescence. These resistant cancer cells possessed a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of a cell culture-based experimental strategy for evaluating anticancer agents, such as JIB-04, that may halt cancer evolution and prevent the development of cancer resistance to currently used therapies.

Advances in colorectal cancer genomics and transcriptomics drive early detection and prevention.

Colorectal carcinoma (CRC) is a high incidence cancer and leading cause of cancer mortality worldwide. The advances in genomics and transcriptomics in the past decades have improved the detection and prevention of CRC in familial CRC syndromes. Nevertheless, the ultimate goal of personalized medicine for sporadic CRC is still not within reach due no less to the difficulty in integrating population disparity and clinical data to combat what essentially is a very heterogenous disease. This minireview highlights the achievement of the past decades and present possible direction in the hope of early detection and metastasis prevention for reducing CRC-associated morbidity and mortality.

Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine.

Highly adaptable breast cancer cells that can opportunistically switch between proliferation and quiescence are often responsible for disease relapse. We have developed a function-based selection strategy for such resistant cells, exemplified by SUM149-MA and FC-IBC02-MA triple-negative breast cancer cells. We have also reported that a lengthy treatment with low-dose 6-mercaptopurine, a clinically useful anti-inflammatory drug, inhibits such resistant cells. To more rigorously test the clinical suitability of 6-mercaptopurine, here we investigated effects of further lowering its dose and the possibility of overcoming resistance to single-drug treatment by combining the drug with another ribonucleoside analog 5-azacitidine. We found that that a lengthy treatment with 1 µM 5-azacitidine, without a significant effect on cell proliferation, sensitized cancer cells to the inhibitory effects of low-dose 6-mercaptopurine. Importantly, treatment for several weeks with low doses of 6-mercaptopurine and/or 5-azacitidine did not render cancer cells resistant to chemotherapeutic drugs doxorubicin or paclitaxel. In fact, the cells became more sensitive to chemotherapeutic drugs upon treatment with 6-mercaptopurine and/or 5-azacitidine. Our analyses of protein markers of epithelial-to-mesenchymal transition indicated that treatments with 6-mercaptopurine and/or 5-azacitidine do not significantly reverse this process in our model. Our results showed that safe drugs such as low-dose 6-mercaptopurine singly or combined with 5-azacitidine, which are suitable for use prior to disease relapse, have a potential of inhibiting highly resistant triple-negative breast cancer cells.

Near-Infrared II Phototherapy Induces Deep Tissue Immunogenic Cell Death and Potentiates Cancer Immunotherapy.

The deep and inner beds of solid tumors lack lymphocytic infiltration and are subjected to various immune escape mechanisms. Reversing immunosuppression deep within the tumor is vital in clinical cancer therapy, however it remains a huge challenge. In this work, we have demonstrated the use of a second window near-infrared (NIR(II)) photothermal treatment to trigger more homogeneous and deeper immunogenic cancer cell death in solid tumors, thereby eliciting both innate and adaptive immune responses for tumor control and metastasis prevention. Specifically, photothermal transducers with similar components, structures, and photothermal conversion efficiencies, but different absorptions in red light, NIR(I), and NIR(II) biowindows, were constructed by controlling the self-assembly of gold nanoparticles on fluidic liposomes. In vitro, photothermal treatments induced immunogenic cell death (ICD) that were accompanied by the release of damage-associated molecular patterns (DAMPs) regardless of the wavelength of incident lasers. In vivo, NIR(II) light resulted in a more homogeneous release and distribution of DAMPs in the deeper parts of the tumors. With the induction of ICD, NIR(II) photothermal therapy simultaneously triggered both innate and adaptive immune responses and enabled efficient tumor control with 5/8 of the mice remaining tumor-free in the cancer vaccination assay. Additionally, the NIR(II) photothermal treatment in combination with checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Finally, using systemically administered two-dimensional polypyrrole nanosheets as a NIR(II) transducer, we achieved striking therapeutic effects against whole-body tumor metastasis via a synergistic photothermal-immunological response.

Nanoparticles Coated with Neutrophil Membranes Can Effectively Treat Cancer Metastasis.

The dissemination, seeding, and colonization of circulating tumor cells (CTCs) serve as the root of distant metastasis. As a key step in the early stage of metastasis formation, colonization of CTCs in the (pre-)metastatic niche appears to be a valuable target. Evidence showed that inflammatory neutrophils possess both a CTC- and niche-targeting property by the intrinsic cell adhesion molecules on neutrophils. Inspired by this mechanism, we developed a nanosize neutrophil-mimicking drug delivery system (NM-NP) by coating neutrophils membranes on the surface of poly(latic-co-glycolic acid) nanoparticles (NPs). The membrane-associated protein cocktails on neutrophils membrane were mostly translocated to the surface of NM-NP via a nondisruptive approach, and the biobinding activity of neutrophils was highly preserved. Compared with uncoated NP, NM-NP exhibited enhanced cellular association in 4T1 cell models under shear flow in vitro, much higher CTC-capture efficiency in vivo, and improved homing to the premetastatic niche. Following loading with carfilzomib, a second generation of proteasome inhibitor, the NM-NP-based nanoformulation (NM-NP-CFZ) selectively depleted CTCs in the blood, prevented early metastasis and potentially inhibited the progress of already-formed metastasis. Our NP design can neutralize CTCs in the circulation and inhibit the formation of a metastatic niche.

Near infrared photoimmunotherapy prevents lung cancer metastases in a murine model.

Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies with the acute toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in preventing lung metastases in a mouse model. Lung is one of the most common sites for developing metastases, but it also has the deepest tissue light penetration. Thus, lung is the ideal site for treating early metastases by using a light-based strategy. In vitro NIR-PIT cytotoxicity was assessed with dead cell staining, luciferase activity, and a decrease in cytoplasmic GFP fluorescence in 3T3/HER2-luc-GFP cells incubated with an anti-HER2 antibody photosensitizer conjugate. Cell-specific killing was demonstrated in mixed 2D/3D cell cultures of 3T3/HER2-luc-GFP (target) and 3T3-RFP (non-target) cells. In vivo NIR-PIT was performed in the left lung in a mouse model of lung metastases, and the number of metastasis nodules, tumor fluorescence, and luciferase activity were all evaluated. All three evaluations demonstrated that the NIR-PIT-treated lung had significant reductions in metastatic disease (*p < 0.0001, Mann-Whitney U-test) and that NIR-PIT did not damage non-target tumors or normal lung tissue. Thus, NIR-PIT can specifically prevent early metastases and is a promising anti-metastatic therapy.

Paving the way for therapeutic prevention of tumor metastasis with agents targeting mitochondrial superoxide.

Metastatic dissemination is associated with poor prognosis of cancer patients. While exploring glucose metabolism in metastatic progenitor cells, we recently found that several different dysfunctions that share the ability to induce mitochondrial superoxide production also promote tumor metastasis. Selective targeting of mitochondrial superoxide prevented spontaneous metastasis in mice, opening a new avenue for therapy.

Quimioterapia Aerossolizada e Pressurizada Intraperitoneal (PIPAC) por monoportal: aplicação alternativa no controle das metástases peritoneais / Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) through a single port: alternative delivery for the control of peritoneal metastases

RESUMO A carcinomatose peritoneal é a evolução natural das neoplasias gastrointestinais, ginecológicas e primárias do peritônio. Nos últimos anos, a carcinomatose passou a ser considerada uma doença confinada ao peritônio, e não mais uma doença disseminada. Desta forma, a associação de citorredução cirúrgica associada à quimioterapia intraperitoneal se tornou o ponto chave no controle das metástases peritoneais. Tradicionalmente, a quimioterapia intraperitoneal é aplicada utilizando soluções líquidas. Uma nova modalidade de infusão da quimioterapia na cavidade abdominal surge como uma alternativa ao método tradicional. A chamada PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy) transforma a solução terapêutica líquida em um spray aerossolizado, potencializando a distribuição e penetração da quimioterapia intraperitoneal. Este relato tem por objetivo descrever essa nova técnica cirúrgica inovadora, realizada pela primeira vez por um monoportal no Brasil, alterando a forma descrita originalmente para a aplicação da PIPAC.

ABSTRACT Peritoneal carcinomatosis is the natural course of gastrointestinal, gynecologic, and primary peritoneal neoplasms. In recent years, our understanding of carcinomatosis has changed; it is no longer considered a disseminated condition, but rather a disease confined to the peritoneum. Thus, the combination of cytoreductive surgery and intraperitoneal chemotherapy has become the cornerstone of control of peritoneal metastases. Traditionally, intraperitoneal chemotherapy is delivered in the form of liquid solutions. However, a new mode of chemotherapy delivery to the abdominal cavity has arisen as an alternative to the conventional method. In Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), the liquid solution is aerosolized into a spray, potentiating the distribution and penetration of the chemotherapeutic agent intraperitoneally. The present study aims to describe a novel form of this innovative surgical technique performed for the first time in Brazil, in a modification of the technique originally described for PIPAC: delivery through a single-port device.

Effect of systemic chemotherapy on conditions of tumor infiltrating, metastasis and disease-specific survival for advanced retinoblastoma / 中华眼底病杂志

Objective To observe the effect of systemic chemotherapy on conditions of tumor infiltrating,metastasis and disease-specific survival (DSS) for advanced retinoblastoma (RB).Methods Forty-one patients with advanced RB who received enucleation were enrolled in this study.There were 26 males and 15 females,age at diagnosis was ranged from 2 to 72 months,with a mean of 23.08 months.There were 16 bilateral patients and 25 unilateral patients;13 group D eyes and 28 group E eyes.16 patients received enucleation as the primary treatment (operation group),25 eyes received chemotherapy before enucleation (chemotherapy group).There was no significant statistical difference between two groups for the gender,unilateral and bilateral,international staging or diagnostic age (P＞0.05).The histopathology report was performed to assess the risk of postoperative tumor-node-metastasis staging (pTNM) in each patient,and the extent of tumor invasion in the optic nerve,choroid and anterior chamber was divided into 3 levels of low risk,medium risk and high risk.Five deaths were all in the group E with chemotherapy before enucleation.Using R software survival analysis software package survfit function,the application of Kaplan-Meier estimation method,DSS of RB children was calculated from the time of diagnosis,up to the date of the death of patient.DSS differences between chemotherapy,operation group and eye removal time (more than 3 months,less than 3 months) in group E RB children were analyzed.Results The proportion of high risk pTNM stage in chemotherapy group was significantly lower than the operation group.But there was no significant difference between the two groups in the overall risk classification (x2 =3.130,P=0.077).For group D eyes,the overall risk classification in chemotherapy group was significantly lower than the operation group (x2 =5.870,P=0.015).There was no significant difference between the two groups in the overall risk of group E eyes (x2 =0.020,P=0.889).The DSS in chemotherapy group and operation group were 0.71 and 1.00,respectively;the difference was significant (x2 =3.700,P=0.05).The DSS in children whose enucleation delayed for more than 3 months and children whose enucleation performed within 3 months were 0.64 and 1.00,respectively;the difference was significant (x2 =4.800,P=0.028).Conclusion Systemic chemotherapy did not reduce the risk of tumor invasion and metastasis in patients with advanced RB.Instead,it will reduce the DSS in group E eyes of RB.