Anti-metastatic Drugs Research Articles

An Insight of Plant Source, Toxicological Profile, and Pharmacological Activities of Iridoid Loganic Acid: A ComprehensiveReview.

This study evaluates the pharmacological effects of iridoid glucoside loganic acid, a plant constituent with diverse properties, based on literature, and explores the underlying cellular mechanisms for treating several ailments. Data were collected from reliable electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar, etc. The results demonstrated the anti-inflammatory, anti-oxidant, and other protective effects of loganic acid on metabolic diseases and disorders such as atherosclerosis, diabetes, and obesity, in addition to its osteoprotective and anticancer properties. The antioxidant activity of loganic acid demonstrates its capacity to protect cells from oxidative damage and mitigates inflammation by reducing the activity of inflammatory cytokines involving TNF-α and IL-6, substantially upregulating the expression of PPAR-γ/α, and decreasing the clinical signs of inflammation-related conditions related to hypertriglyceridemia and atherosclerosis. Meanwhile, loganic acid inhibits bone loss, exhibits osteoprotective properties by increasing mRNA expression levels of bone synthesizing genes such as Alpl, Bglap, and Sp7, and significantly increases osteoblastic proliferation in preosteoblast cells. Loganic acid is an anti-metastatic drug that reduces MnSOD expression, inhibits EMT and metastasis, and prevents cellular migration, proliferation, and invasion in hepatocellular carcinoma cells. However, additional clinical trials are required to assess its safety, efficacy, and human dose.

Real-time label-free three-dimensional invasion assay for anti-metastatic drug screening using impedance sensing.

Tumor metastasis presents a formidable challenge in cancer treatment, necessitating effective tools for anti-cancer drug development. Conventional 2D cell culture methods, while considered the "gold standard" for invasive studies, exhibit limitations in representing cancer hallmarks and phenotypes. This study proposes an innovative approach that combines the advantages of 3D tumor spheroid culture with impedance-based biosensing technologies to establish a high-throughput 3D cell invasion assay for anti-metastasis drug screening through multicellular tumor spheroids. In addition, the xCELLigence device is employed to monitor the time-dependent kinetics of cell behavior, including attachment and invasion out of the 3D matrix. Moreover, an iron chelator (deferoxamine) is employed to monitor the inhibition of epithelial-mesenchymal transition in 3D spheroids across different tumor cell types. The above results indicate that our integrated 3D cell invasion assay with impedance-based sensing could be a promising tool for enhancing the quality of the drug development pipeline by providing a robust platform for predicting the efficacy and safety of anti-metastatic drugs before advancing into preclinical or clinical trials.

Cellular Traction Force Holds the Potential as a Drug Testing Readout for In Vitro Cancer Metastasis

IntroductionMetastasis is responsible for 90% of cancer-related deaths worldwide. However, the potential inhibitory effects of metastasis by various anticancer drugs have been left largely unexplored. Existing preclinical models primarily focus on antiproliferative agents on the primary tumor to halt the cancer growth but not in metastasis. Unlike primary tumors, metastasis requires cancer cells to exert sufficient cellular traction force through the actomyosin machinery to migrate away from the primary tumor site. Therefore, we seek to explore the potential of cellular traction force as a novel readout for screening drugs that target cancer metastasis.MethodsIn vitro models of invasive and non-invasive breast cancer were first established using MDA-MB-231 and MCF-7 cell lines, respectively. Cellular morphology was characterized, revealing spindle-like morphology in MDA-MB-231 and spherical morphology in MCF-7 cells. The baseline cellular traction force was quantified using the Traction force Microscopy technique. Cisplatin, a paradigm antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, were selected to evaluate the potential of cellular traction force as a drug testing readout for the in vitro cancer metastasis.ResultsMDA-MB-231 cells exhibited significantly higher baseline cellular traction force compared to MCF-7 cells. Treatment with Cisplatin, an antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, demonstrated distinct effects on cellular traction force in MDA-MB-231 but not in MCF-7 cells. These findings correlate with the invasive potential observed in the two models.ConclusionCellular traction force emerges as a promising metric for evaluating drug efficacy in inhibiting cancer metastasis using in vitro models. This approach could enhance the screening and development of novel anti-metastatic therapies, addressing a critical gap in current anticancer drug research.

Lysophosphatidic Acid Receptor 1 (LPA1) Antagonists as Potential Migrastatics for Triple Negative Breast Cancer.

Metastasis is responsible for about 90 % of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA1) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compound 12 f, the most potent and highly selective in this series with an IC50 value of 16.0 nM in the cAMP assay and 18.4 nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBC cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA1 as a migrastatic target. Consequently, the LPA1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC.

Decoding the interplay between genetic and non-genetic drivers of metastasis.

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.

A Microfluidics-Assisted Double-Barreled Nanobioconjugate Synthesis Introducing Aprotinin as a New Moonlight Nanocarrier Protein: Tested toward Physiologically Relevant 3D-Spheroid Models.

Proteins are promising substances for introducing new drug carriers with efficient blood circulation due to low possibilities of clearance by macrophages. However, such natural biopolymers have highly sophisticated molecular structures, preventing them from being assembled into nanoplatforms with manipulable payload release profiles. Here, we report a novel anticancer nanodrug carrier moonlighting protein, Aprotinin, to be used as a newly identified carrier for cytotoxic drugs. The Aprotinin-Doxorubicin (Apr-Dox) nanobioconjugate was prepared via a single-step microfluidics coflow mixing technique, a feasible and simple way to synthesize a carrier-based drug design with a double-barreled approach that can release and actuate two therapeutic agents simultaneously, i.e., Apr-Dox in 1:11 ratio (the antimetastatic carrier drug aprotinin and the chemotherapeutic drug DOX). With a significant stimuli-sensitive (i.e., pH) drug release ability, this nanobioconjugate achieves superior bioperformances, including high cellular uptake, efficient tumor penetration, and accumulation into the acidic tumor microenvironment, besides inhibiting further tumor growth by halting the urokinase plasminogen activator (uPA) involved in metastasis and tumor progression. Distinctly, in healthy human umbilical vein endothelial (HUVEC) cells, drastically lower cellular uptake of nanobioconjugates has been observed and validated compared to the anticancer agent Dox. Our findings demonstrate an enhanced cellular internalization of nanobioconjugates toward breast cancer, prostate cancer, and lung cancer both in vitro and in physiologically relevant biological 3D-spheroid models. Consequently, the designed nanobioconjugate shows a high potential for targeted drug delivery via a natural and biocompatible moonlighting protein, thus opening a new avenue for proving aprotinin in cancer therapy as both an antimetastatic and a drug-carrying agent.

Abstract 5423: Selective inhibition of glucose transporter 3 (GLUT3) suppresses triple-negative breast cancer cell migration by modulating actin cytoskeleton and cell mechanics

Abstract Studies have reported clear clinical observations indicating that obesity and diabetes, which often accompany hyperglycemia, are linked to a poor prognosis across various types of cancer. Specifically, multiple clinical studies involving breast cancer patients have demonstrated that hyperglycemia (>7 mM) is associated with an unfavorable prognosis. Despite the evident correlation between elevated glucose levels and cancer metastasis, the causality remains unclear, and the underlying molecular mechanisms are largely unknown. In both normal and diseased physiology, a broad range of tissue glucose levels has been documented, ranging from normal blood circulation (5.5 mM) to normal tissues (1 - 3 mM) and to tumor tissues (<0.5 mM). Consequently, during the early stages of metastasis, cancer cells undergo a significant increase in extracellular glucose levels. The capacity of cancer cells to deform and exert contractile force, collectively known as cell mechanics, plays a crucial role in various stages of metastasis. In our previous work, we demonstrated that elevated extracellular glucose levels boost glycolysis and activate the RhoA signaling pathway. This leads to heightened cell stiffness and increased contractility in human triple-negative breast cancer (TNBC) cells. Furthermore, the modified cell mechanics are associated with enhanced cell migration and invasion. In this study, we present findings indicating that the inhibition of glucose transporter 3 (GLUT3) significantly diminishes the motility of human TNBC cells, including MDA-MB-231 and its highly metastatic variant, MDA-MB-231/HM cells. Mechanistic investigations reveal that GLUT3 inhibition, facilitated by a well-characterized potent GLUT3-selective inhibitor (G3iA), results in reduced glucose uptake and glycolysis. The diminished glycolysis, induced by GLUT3 inhibition, activates 5' AMP-activated protein kinase (AMPK) and enhances the phosphorylation of Yes-associated protein (YAP). Moreover, GLUT3 inhibition leads to a decrease in non-muscle myosin II activity and induces alterations in F-actin rearrangement by influencing actin-binding proteins such as VASP and cofilin. These changes are associated with a reduction in cell migration. In summary, our results suggest that inhibiting GLUT3 modifies the mechanics of TNBC cells, leading to a decrease in cell motility. Given that GLUT3 is notably elevated in TNBC and is linked to metastatic progression and a poor prognosis in breast cancer patients, our findings underscore the need for further in vivo studies to validate G3iA as a potential anti-metastatic drug in hyperglycemic TNBC animal models. Citation Format: Tae-Hyung Kim, Aadil Qadir Bhat, Cristina V. Iancu, Jun-Yong Choe. Selective inhibition of glucose transporter 3 (GLUT3) suppresses triple-negative breast cancer cell migration by modulating actin cytoskeleton and cell mechanics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5423.

Phytochemical composition of the diethyl ether extract of Artemisia lactiflora Wall. ex DC and its antimetastatic activity in human lung cancer cells

Artemisia lactiflora Wall. ex DC. is a traditional Chinese medicinal plant used in the treatment of menstrual and hepatic disorders due to its antioxidant and anti-inflammatory properties. However, its anti-metastatic activity, which is the clinical challenge of lung cancer treatment, has not yet been reported. From the diethyl ether extract of Artemisia lactiflora, the four terpenoids, including dihydroactinidiolide, megastigmatrienone, alpha-curcumene, and dehydrovomifoliol, were the most intense peaks observed using LC-MS/MS, whereas bis (2-ethylhexyl) phthalate was a contaminant. In a transwell assay, the A. lactiflora diethyl ether extract (32 μg/ml) and dihydroactinidiolide (250 μg/ml) markedly inhibited the migration and invasion of non-small cell lung cancer (NSCLC) cells, similar to the standard anti-metastatic drug (capmatinib). Western blot analysis revealed that mesenchymal N-cadherin is downregulated in NSCLC cells under the treatment conditions. The potential anti-metastatic property of dihydroactinidiolide is promising as a new candidate anti-metastatic agent for lung cancer treatment.

Development of Anti-metastatic Drugs Based on Banned Imide-Polyamine Conjugates and Their Application in The Treatment of Liver Cancer

The purpose of this study was to develop an anti-metastasis drug based on a banned imide-polyamine conjugate and to explore its application in the treatment of liver cancer. First, we designed and synthesized a series of forbidden imide-polyamine conjugates and evaluated their inhibitory effects on the migration and invasion capacity of HCC cells by cell assay. The results showed that these compounds were able to significantly reduce the metastatic ability of HCC cells. Further mechanistic studies revealed that these compounds are able to inhibit the metastasis of HCC cells by interfering with intracellular signaling pathways and affecting cytoskeletal reorganization. These compounds also showed promising anti-HCC metastatic effects in animal models. To further optimize the structure and activity of these compounds, we optimized their structures using computer-aided design techniques. Through molecular docking and molecular dynamics simulations, we found a number of compounds with higher activity and selectivity. These optimized compounds further validate their anti-metastatic effect in cellular experiments and have less effect on normal cells, showing better biocompatibility. We also explored the mechanism of action of these compounds in HCC treatment. These compounds were found to be able to induce apoptosis in HCC cells and to inhibit their proliferation. At the same time, they can also promote the autophagy and cell cycle arrest of HCC cells, thus inhibiting the development of HCC in many ways. The forbidden imide-polyamine conjugates developed in this study have the potential to serve as novel anti-HCC metastasis agents. In the future, we will continue to optimize the structure and activity of these compounds and conduct clinical trials to validate their efficacy and safety. In addition, we will further explore the mechanisms of these compounds in order to provide new strategies for the prevention and treatment of HCC.

RBMS1 Coordinates with the m6A Reader YTHDF1 to Promote NSCLC Metastasis through Stimulating S100P Translation.

Metastasis is the leading cause for the high mortality of lung cancer, however, effective anti-metastatic drugs are still limited. Here it is reported that the RNA-binding protein RBMS1 is positively associated with increased lymph node metastasis in non-small cell lung cancer (NSCLC). Depletion of RBMS1 suppresses cancer cell migration and invasion in vitro and inhibits cancer cell metastasis in vivo. Mechanistically, RBMS1 interacts with YTHDF1 to promote the translation of S100P, thereby accelerating NSCLC cell metastasis. The RRM2 motif of RBMS1 and the YTH domain of YTHDF1 are required for the binding of RBMS1 and YTHDF1. RBMS1 ablation inhibits the translation of S100P and suppresses tumor metastasis. Targeting RBMS1 with NTP, a small molecular chemical inhibitor of RBMS1, attenuates tumor metastasis in a mouse lung metastasis model. Correlation studies in lung cancer patients further validate the clinical relevance of the findings. Collectively, the study provides insight into the molecular mechanism by which RBMS1 promotes NSCLC metastasis and offers a therapeutic strategy for metastatic NSCLC.

IL-1 Family Members in Bone Sarcomas.

IL-1 family members have multiple pleiotropic functions affecting various tissues and cells, including the regulation of the immune response, hematopoietic homeostasis, bone remodeling, neuronal physiology, and synaptic plasticity. Many of these activities are involved in various pathological processes and immunological disorders, including tumor initiation and progression. Indeed, IL-1 family members have been described to contribute to shaping the tumor microenvironment (TME), determining immune evasion and drug resistance, and to sustain tumor aggressiveness and metastasis. This review addresses the role of IL-1 family members in bone sarcomas, particularly the highly metastatic osteosarcoma (OS) and Ewing sarcoma (EWS), and discusses the IL-1-family-related mechanisms that play a role in bone metastasis development. We also consider the therapeutic implications of targeting IL-1 family members, which have been proposed as (i) relevant targets for anti-tumor and anti-metastatic drugs; (ii) immune checkpoints for immune suppression; and (iii) potential antigens for immunotherapy.

Antimetastatic Drug, Pharmacologic Challenge and Opportunity

Abstracts: Cancer is a complex and high-mortality disease in the clinic. Cancer metastasis leads to most cancer deaths. The therapeutics for cancer metastasis are greatly unsatisfactory now. Despite different types of antimetastatic agents and drugs have been reported, 90% of patients die in 5 years after metastatic nodules at secondary sites have been found. : Many pharmacologic challenges and opportunities for current metastasis therapies are presented. To overcome the dilemma and shortcomings of antimetastatic treatment, medical, chemical, pharmaceutical, methodological and technical issues are integrated and highlighted. To introduce up-to-date knowledge and insights into drug targeting and pharmaceutical features and clinical paradigms, relevant drug design insights are discussed—including different pathological modes, diagnosis advances, metastatic cascade, tumor plasticity, variety of animal models, therapeutic biomarkers, computational tools and cancer genomics. Integrated knowledge, systems and therapeutics are focused. : In summary, medicinal comparison, pharmaceutical innovation and clinical strategies should be increasingly investigated.

Linking cell mechanical memory and cancer metastasis.

Metastasis causes most cancer-related deaths; however, the efficacy of anti-metastatic drugs is limited by incomplete understanding of the biological mechanisms that drive metastasis. Focusing on the mechanics of metastasis, we propose that the ability of tumour cells to survive the metastatic process is enhanced by mechanical stresses in the primary tumour microenvironment that select for well-adapted cells. In this Perspective, we suggest that biophysical adaptations favourable for metastasis are retained via mechanical memory, such that the extent of memory is influenced by both the magnitude and duration of the mechanical stress. Among the mechanical cues present in the primary tumour microenvironment, we focus on high matrix stiffness to illustrate how it alters tumour cell proliferation, survival, secretion of molecular factors, force generation, deformability, migration and invasion. We particularly centre our discussion on potential mechanisms of mechanical memory formation and retention via mechanotransduction and persistent epigenetic changes. Indeed, we propose that the biophysical adaptations that are induced by this process are retained throughout the metastatic process to improve tumour cell extravasation, survival and colonization in the distant organ. Deciphering mechanical memory mechanisms will be key to discovering a new class of anti-metastatic drugs.

Invasion-Block and S-MARVEL: A high-content screening and image analysis platform identifies ATM kinase as a modulator of melanoma invasion and metastasis.

Robust high-throughput assays are crucial for the effective functioning of a drug discovery pipeline. Herein, we report the development of Invasion-Block, an automated high-content screening platform for measuring invadopodia-mediated matrix degradation as a readout for the invasive capacity of cancer cells. Combined with Smoothen-Mask and Reveal, a custom-designed, automated image analysis pipeline, this platform allowed us to evaluate melanoma cell invasion capacity posttreatment with two libraries of compounds comprising 3840 U.S. Food and Drug Administration (FDA)-approved drugs with well-characterized safety and bioavailability profiles in humans as well as a kinase inhibitor library comprising 210 biologically active compounds. We found that Abl/Src, PKC, PI3K, and Ataxia-telangiectasia mutated (ATM) kinase inhibitors significantly reduced melanoma cell invadopodia formation and cell invasion. Abrogation of ATM expression in melanoma cells via CRISPR-mediated gene knockout reduced 3D invasion in vitro as well as spontaneous lymph node metastasis in vivo. Together, this study established a rapid screening assay coupled with a customized image-analysis pipeline for the identification of antimetastatic drugs. Our study implicates that ATM may serve as a potent therapeutic target for the treatment of melanoma cell spread in patients.

Comparative analysis of the use of B16 melanoma and epidermoid Lewis lung carcinoma models for preclinical studies of compounds with a putative antitumor effect

Introduction The search for new compounds with putative antitumor effects and the development of domestic anticancer and antimetastatic drugs based on them is a priority task for specialists in the field of medical chemistry, experimental pathophysiology and pharmacology. Melanoma B16 and Lewis lung epidermoid carcinoma are universal models for evaluating the effect of compounds with putative antitumor action on the primary focus of tumor growth and the process of tumor cells dissemination.The aim of the work is to determine the feasibility of using models of solid tumor growth and metastasis activity of Lewis lung epidermoid carcinoma and B16 melanoma for preclinical studies of antitumor and antimetastatic pharmacological activity of hybrid organotin compounds depending on experimental objectives.Materials and methods The experimental part was performed on C57B1/6 mice (females). Hybrid organotin compounds were administered five times, intraperitoneal, the beginning of treatment – 48 hours after tumor cells transplantation in the same regimes for both models. In this work, the most effective (375 mg/kg and 250 mg/kg, respectively) and toxic (500 mg/kg and 375 mg/kg, respectively) doses of the leader hybrid organotin compounds Me3 (bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethytin) and Me5 ((3,5-di-tert-butyl-4-hydroxyphenylthiolate)triphenyltin) were used.Results At all stages of the experiment on both models of tumor growth we obtained similar results characterizing the pharmacological activity of the tested compounds: moderate antitumor and high antimetastatic effect. The rates of growth and tumor process development are comparable and convenient for planning preclinical studies in vivo and can be interchangeable.Discussion The Lewis lung model of epidermoid carcinoma has a higher degree of convenience for data interpretation (number of metastatic foci in the lungs) when conducting exploratory analysis of pharmacological activity in a wide range of doses. When studying pathogenetic peculiarities of metastasis under the action of compounds with presumed antitumor action due to the possibilities of contrast immunohistochemical staining of tumor cells, the B16 melanoma model has an advantage. In our experiment with immunohistochemical staining for Melan A the hematogenic pathway of metastasis through the bloodstream is clearly traced.Conclusion For exploratory screening studies to select promising candidates for in-depth study it is reasonable to use the Lewis lung epidermoid carcinoma model. The B16 melanoma model is more informative for in-depth study of compounds that have proven to be effective.

Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis

Metastasis is directly linked to poor prognosis of cancer patients and warrants search for effective anti-metastatic drugs. MACC1 is a causal key molecule for metastasis. High MACC1 expression is prognostic for metastasis and poor survival. Here, we developed novel small molecule inhibitors targeting MACC1 expression to impede metastasis formation. We performed a human MACC1 promoter-driven luciferase reporter-based high-throughput screen (HTS; 118.500 compound library) to identify MACC1 transcriptional inhibitors. HTS revealed 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds as efficient transcriptional inhibitors of MACC1 expression, able to decrease MACC1-induced cancer cell motility in vitro. Structure-activity relationships identified the essential inhibitory core structure. Best candidates were evaluated for metastasis inhibition in xenografted mouse models demonstrating metastasis restriction. ADMET showed high drug-likeness of these new candidates for cancer therapy. The NFκB pathway was identified as one mode of action targeted by these compounds. Taken together, 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds are effective MACC1 inhibitors and pose promising candidates for anti-metastatic therapies particularly for patients with MACC1-overexpressing cancers, that are at high risk to develop metastases. Although further preclinical and clinical development is necessary, these compounds represent important building blocks for an individualized anti-metastatic therapy for solid cancers.

Патогенетические аспекты введения соединений с предполагаемым противоопухолевым действием в метрономном режиме (обзор)

Chemotherapy is the main treatment method for malignant neoplasms. Classical administration regimens for chemotherapeutic agents are accompanied by strong side effects. Thus, there is a need for a rational mode of administration that can increase the effectiveness of chemotherapy and reduce its side effects. Development of new antitumour drugs must involve testing their pharmacological activity at various administration regimens. At the stage of preclinical studies of new compounds with an alleged antitumour effect, determining an optimal dosage regimen is an urgent task for interdisciplinary research. This article analyses literature on the possible use and effectiveness of metronomic administration of antitumour drugs in clinical practice and in preclinical studies depending on the pathogenetic mechanism of their action. According to recent research, metronomic administration of antitumour and antimetastatic drugs is, undoubtedly, a rational way to solve the problem of severe side effects and poor drug tolerability in cancer patients. The greatest antitumour effectiveness in the metronomic regimen is achieved at combined administration of compounds with different mechanisms of action. In preclinical studies of new antitumour agents, it is important to adhere to the basic principles of developing a metronomic administration regimen: 1) at the testing stage, it is advisable to perform screening administration of low doses of new compounds along with a therapy with a known antitumour drug; 2) the minimum dose of the new compound can be calculated using its maximum tolerated dose (initial approximate series of administration in the amount of 1/10 of the maximum tolerated dose).

Small Molecules against Metastatic Tumors: Concrete Perspectives and Shattered Dreams.

Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.

Gastric cancer modeling in immunodeficient mice with orthotopic xenotransplantation

Purpose of the study. Creation of a transplantable orthotopic PDX model of gastric cancer in Balb/c Nude immunodeficient mice using implantation and injection.Materials and methods. Two methods, that are injection and implantation, were used to create an orthotopic PDX model of human gastric cancer. The first method involved injections of a suspension of a mechanically disaggregated patient's tumor after filtration into the gastric wall of Balb/c Nude mice. For the second method, small fragments (3 × 3 × 3 mm) of patients' tumors were implanted in the gastric wall of mice along the greater curvature with a dissection of the serous muscular layer.Results. Control laparotomy in Balb/c Nude immunodeficient mice showed a successful engraftment of the tumor material at the 1st and 3rd procedures when using the implantation method for the creation of a PDX model of gastric cancer. The injection method was ineffective, and no models were created. The histological type of the obtained PDX models was compared to the type of the donor tumor by histological examination (hematoxylin and eosin staining). The tumor grade remained stable and did not change during xenograft passage, which showed that the obtained model was identical to the histotype of the donor tumor.Conclusion. The presented implantation method for the model creation results in effective tumor engraftment. The developed model can be used to test the effectiveness of anticancer or antimetastatic drugs, for studying the functions of biomarkers, or in assessing the microenvironment of a gastric cancer.

Anti-metastatic drug development, overview and perspectives

Introduction: Neoplasm metastasis is a multiple-step and multi-component involved pathogenesis causing large human mortality and socioeconomic burden. Currently, anti-metastatic drugs are the widest therapeutic targets for clinical cancer trials. The most effective drugs are yet to be developed. Methods: Anti-metastatic drugs are evaluated by a great variety of tumor models and cutting-edge biotechnology. Anti-metastatic drug evaluation and development is still a pharmaceutical challenge worldwide. Many technical deficit and knowledge limitation has been overcoming decade by decade. Discussion: Different aspects of chemical, pathologic, pharmacological and pharmaceutical knowledge breakthroughs for neoplasm metastasis evaluation are discussed. Better knowledge for the complexity of metastasis pathology is essential for therapeutic moving forward. Conclusion: A great therapeutic responses and benefits can be expected after aforementioned biomedical study, technical progression and drug development.