Insights into the Mechanisms of Action of MDA-7/IL-24: A Ubiquitous Cancer-Suppressing Protein

Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), a secreted protein of the IL-10 family, was first identified more than two decades ago as a novel gene differentially expressed in terminally differentiating human metastatic melanoma cells. MDA-7/IL-24 functions as a potent tumor suppressor exerting a diverse array of functions including the inhibition of tumor growth, invasion, angiogenesis, and metastasis, and induction of potent “bystander” antitumor activity and synergy with conventional cancer therapeutics. MDA-7/IL-24 induces cancer-specific cell death through apoptosis or toxic autophagy, which was initially established in vitro and in preclinical animal models in vivo and later in a Phase I clinical trial in patients with advanced cancers. This review summarizes the history and our current understanding of the molecular/biological mechanisms of MDA-7/IL-24 action rendering it a potent cancer suppressor.

Effect of Low-molecular Pectin and Metformin on Paclitaxel Toxicity in Rats with Walker Carcinosarcoma

Recently, researchers have been particularly interested in the use of herbal agents in combination therapy of tumors with a spectrum of regulatory effects, low toxicity, and high bioavailability, as well as drugs that indirectly affect the growth and metastasis of tumor cells. The article presents the results of experiments on the study of the combined effect of metformin, low molecular weight pectin and cytostatic agent — paclitaxel on the transplantable tumor — Walker’s carcinosarcoma 256, in order to reduce the toxic effect of the chemotherapy drug. With the combined administration of pectin and paclitaxel (10 mg/kg), metformin and paclitaxel (10 mg/kg), inhibition of tumor growth was observed. On the 25th day, the death of 50% of the animals was observed in the first group, and in the remaining 50%, complete tumor regression was observed. With a single administration of paclitaxel at a single dose of 10 mg / kg of live weight, 62.5% of the animals died in the first 4 days. The combination of drugs (pectin + metformin + paclitaxel) at various single doses of paclitaxel (10, 20, and 25 mg/kg) had an antagonistic effect, showing worse results than the use of each drug with a cytostatic alone (death of animals in the period from 1 to 6 days). Thus, the experimental results demonstrated a clear toxicity reduction effect at high doses of paclitaxel in combination with pectin or metformin.

Psoralen-loaded polymeric lipid nanoparticles combined with paclitaxel for the treatment of triple-negative breast cancer

Background: Chemotherapeutic drugs are associated with toxic effects. Metastasis is the leading cause of death in breast cancer patients. Aim: To evaluate the antitumor effect of paclitaxel (PTX) combined with psoralen-loaded polymeric lipid nanoparticles (PSO-PLNs) in triple-negative breast cancer. Methods: After treatment of samples, cell viability, apoptosis, migration, invasion, expression of proteins in the IRAK1/NF-κB/FAK signal pathway, biodistribution and pathological characteristics were detected. Results: Compared with the control group, the PTX + PSO-PLNs group showed increased apoptosis and reduced migration, invasion and expression of phosphorylated IRAK1 and NF-κB, with significant inhibition of tumor growth and lung metastases and no obvious toxicity. Conclusion: Combined administration of PTX and PSO-PLNs exerted a synergistic effect and significantly inhibited the growth and metastasis of triple-negative breast cancer.

Modulation of Long Non-Coding RNAs by Different Classes of Secondary Metabolites from Plants: A Mini-Review on Antitumor Effects

: The broad pharmacological spectrum of plants is related to their secondary metabolism, which is responsible for the synthesis of different compounds that have multiple effects on cellular physiology. Among the biological effects presented by phytochemicals, their use for the prevention and treatment of cancer can be highlighted. This occurs due to several mechanisms of antitumor action demonstrated by these compounds, including regulation of the cell signaling pathways and inhibition of tumor growth. In this way, long non-coding RNAs (lncRNAs) appear to be promising targets for the treatment of cancer. Their deregulation has already been related to a variety of clinical-pathological parameters. However, the effects of secondary metabolites on lncRNAs are still restricted. For this reason, the present review aimed to gather data on phytochemicals with action on lncRNAs in order to confirm their possible antitumor potential. According to the literature, terpenoid and flavonoid are the main examples of secondary metabolites involved with lncRNAs activity. In addition, the lncRNAs H19, CASC2, HOTAIR, NKILA, CCAT1, MALAT1, AFAP1-AS1, MEG3, and CDKN2B-AS1 can be highlighted as important targets in the search for new anti-tumor agents since they act as modulating pathways related to cell proliferation, cell cycle, apoptosis, cell migration and invasion. Finally, challenges for the use of natural products as a commercial drug were also discussed. The low yield, selectivity index and undesirable pharmacokinetic parameters were emphasized as a difficulty for obtaining these compounds on a large scale and for improving the potency of its biological effect. However, the synthesis and/or development of formulations were suggested as a possible approach to solve these problems. All of these data together confirm the potential of secondary metabolites as a source of new anti-tumor agents acting on lncRNAs.

947 Recombinant myxoma virus MC509-N1 demonstrates antitumor efficacy as monotherapy and in combination with immune checkpoint inhibitors

BackgroundThere are several obstacles to effective cancer immunotherapy including the heterogenic immune profile and the state of the tumor microenvironment. Oncolytic virotherapy provides an opportunity to overcome some of these limitations through high viral replication and the expression of therapeutic transgenes (TGs) within the tumor tissue. Myxoma virus (MYXV) belongs to the family of Poxviridae and represents a potent oncolytic virus and a safe platform as this virus is non-pathogenic in any hosts apart from lagomorphs. Importantly, MYXV has a high capacity of encoding for multiple TG payloads. Here we engineered MC509-N1, a novel double-encoding transgenes (TG1 and TG2) oncolytic MYXV designed for intravenous (IV) injection. The therapeutic TG1 acts to modify and remodel the immune state of the tumor microenvironment, and TG2 allows for prolonged self-evasion from the host immune defense.MethodsTransgenes expression upon infection was detected by ELISA and by flow cytometry. To determine anticancer efficacy, syngeneic B16F10 melanoma or MC38 colorectal cancer-bearing C57BL/6 mice were injected with MC509-N1 intratumorally or IV with or without immune checkpoint inhibitor (ICI). Tumor growth and survival was monitored after treatment and the immune profile within the tumor microenvironment was analyzed by flow cytometry. Mice cured of their tumors from the original treatment were rechallenged with primary tumor cells to examine anticancer immunity.ResultsCells upon infection with MC509-N1 were found to express both transgenes at high levels and stimulate downstream mechanisms. Importantly, the engineering of both transgenes did not affect MC509-N1 infectivity and productivity as compared to wild-type MYXV. Intratumoral injections of MC509-N1 effectively suppressed tumor growth and improved overall survival of both syngeneic cancer models. Furthermore, MC509-N1 therapy effectively modulated the immune profile within the tumor microenvironment, especially the ratio between tumor infiltrated CD8+ cytotoxic T cells and CD4+FoxP3+ T regulatory cells. In addition, IV injections of MC509-N1 showed improved inhibition of tumor growth compared to wild type MYXV. The combination therapy of MC509-N1 with the ICI anti-PD-L1 further promoted inhibition of tumor growth as demonstrated by higher rate of complete regression and improved survival rate. Furthermore, rechallenge experiments revealed that this combination regimen established specific anticancer immune memory and protected from cancer recurrence.ConclusionsOur results demonstrate that the novel engineered MC509-N1 exhibits potent anticancer efficacy, adequately modulates the immune state of the tumor microenvironment, and acts synergistically to eliminate cancer in combination with ICI.

EFFECTS OF 5-HYDROXYPYRIMIDINE DERIVATIVE ON GROWTH AND METASTASIS OF MELANOMA B16 IN C57BL/6 MICE

Introduction. Suppression of activation of an alternative immune response is promising approach of tumor immunotherapy. In this study we evaluated antitumor and antimetastatic activity of SNK-411.Objective. Evaluation of antitumor and antimetastatic activity of 5-hydroxypyrimidine derivative SNK-411 in mouse melanoma B16 model.Materials and methods. Antitumor and antimetastatic activity of the SNK-411 were studied in tests on male C57BL/6 mice using the B16-F10 melanoma model. SNK-411 was injected intraperitoneally at doses of 10 and 25 mg/kg from day 2 to day 15 of melanoma development. Doxorubicin was injected at dose of 4 mg/kg on day 2 of tumor development to act as positive control. Antitumor and antimetastatic activity were studied by calculation of tumor growth inhibition and metastasis inhibition index (MII).Results. SNK-411 at doses of 10 and 25 mg/kg and in combination with single injection of doxorubicin in dose of 4 mg/kg showed antimetastatic activity. MII in SNK-411 at 10 mg/kg dose was 72 %, at dose of 25 mg/kg was 82,9 %. The combination of 14-day course of intraperitoneal injections of SNK-411 at dose of 10 mg/kg and injection of doxorubicin 4 mg/kg revealed MII 97,1 %, in half of mice in this group metastasis were not observed on 21st day of melanoma development. All results are statistically significant. There was no significant inhibition of tumor growth in all groups.Conclusion. SNK-411 has antimetastatic activity in tests on melanoma B16 model. Further investigation is required.

Mesenchymal stromal cells as carriers of IL-12 reduce primary and metastatic tumors of murine melanoma

Due to immunosuppressive properties and confirmed tropism towards cancer cells mesenchymal stromal cells (MSC) have been used in many trials. In our study we used these cells as carriers of IL-12 in the treatment of mice with primary and metastatic B16-F10 melanomas. IL-12 has confirmed anti-cancer activity, induces a strong immune response against cancer cells and acts as an anti-angiogenic agent. A major limitation of the use of IL-12 in therapy is its systemic toxicity. The aim of the work was to develop a system in which cytokine may be administered intravenously without toxic side effects. In this study MSC were used as carriers of the IL-12. We confirmed antitumor effectiveness of the cells secreting IL-12 (MSC/IL-12) in primary and metastatic murine melanoma models. We observed inhibition of tumor growth and a significant reduction in the number of metastases in mice after MSC/IL-12 administration. MSC/IL-12 decreased vascular density and increased the number of anticancer M1 macrophages and CD8+ cytotoxic T lymphocytes in tumors of treated mice. To summarize, we showed that MSC are an effective, safe carrier of IL-12 cytokine. Administered systemically they exert therapeutic properties of IL-12 cytokine without toxicity. Therapeutic effect may be a result of pleiotropic (proinflammatory and anti-angiogenic) properties of IL-12 released by modified MSC.

Peroxisome inspired hybrid enzyme nanogels for chemodynamic and photodynamic therapy

Peroxisome, a special cytoplasmic organelle, possesses one or more kinds of oxidases for hydrogen peroxide (H2O2) production and catalase for H2O2 degradation, which serves as an intracellular H2O2 regulator to degrade toxic peroxides to water. Inspired by this biochemical pathway, we demonstrate the reactive oxygen species (ROS) induced tumor therapy by integrating lactate oxidase (LOx) and catalase (CAT) into Fe3O4 nanoparticle/indocyanine green (ICG) co-loaded hybrid nanogels (designated as FIGs-LC). Based on the O2 redistribution and H2O2 activation by cascading LOx and CAT catalytic metabolic regulation, hydroxyl radical (·OH) and singlet oxygen (1O2) production can be modulated for glutathione (GSH)-activated chemodynamic therapy (CDT) and NIR-triggered photodynamic therapy (PDT), by manipulating the ratio of LOx and CAT to catalyze endogenous lactate to produce H2O2 and further cascade decomposing H2O2 into O2. The regulation reactions of FIGs-LC significantly elevate the intracellular ROS level and cause fatal damage to cancer cells inducing the effective inhibition of tumor growth. Such enzyme complex loaded hybrid nanogel present potential for biomedical ROS regulation, especially for the tumors with different redox state, size, and subcutaneous depth.

Clinical, genetic and pharmacological data support targeting the MEK5/ERK5 module in lung cancer

Despite advances in its treatment, lung cancer still represents the most common and lethal tumor. Because of that, efforts to decipher the pathophysiological actors that may promote lung tumor generation/progression are being made, with the final aim of establishing new therapeutic options. Using a transgenic mouse model, we formerly demonstrated that the sole activation of the MEK5/ERK5 MAPK route had a pathophysiological role in the onset of lung adenocarcinomas. Given the prevalence of that disease and its frequent dismal prognosis, our findings opened the possibility of targeting the MEK5/ERK5 route with therapeutic purposes. Here we have explored such possibility. We found that increased levels of MEK5/ERK5 correlated with poor patient prognosis in lung cancer. Moreover, using genetic as well as pharmacological tools, we show that targeting the MEK5/ERK5 route is therapeutically effective in lung cancer. Not only genetic disruption of ERK5 by CRISPR/Cas9 caused a relevant inhibition of tumor growth in vitro and in vivo; such ERK5 deficit augmented the antitumoral effect of agents normally used in the lung cancer clinic. The clinical correlation studies together with the pharmacological and genetic results establish the basis for considering the targeting of the MEK5/ERK5 route in the therapy for lung cancer.

IL7-Fc Enhances the Efficacy of Adoptive T Cell Therapy under Lymphopenic Conditions in a Murine Melanoma Model

Adoptive cell therapy (ACT) using tumor-reactive T cells is a promising form of immunotherapy to specifically target cancer. However, the survival and functional maintenance of adoptively transferred T cells remains a challenge, ultimately limiting their efficacy. Here, we evaluated the use of recombinant IL7-Fc in ACT. In a lymphopenic murine melanoma model, IL7-Fc treatment led to the enhanced inhibition of tumor growth with an increased number of adoptively transferred CD8+ T cells in tumor tissue and tumor-draining lymph nodes. Additionally, IL7-Fc further enhanced anti-tumor responses that were induced by recombinant human IL2 in the same mouse model. In contrast, in an immunocompetent murine melanoma model, IL7-Fc dampened the anti-tumor immunity. Further, IL7-Fc decreased the proliferation of adoptively transferred and immune-activated tumor-reactive CD8+ T cells in immunocompetent mice by inducing the massive expansion of endogenous T cells, thereby limiting the space for adoptively transferred T cells. Our data suggest that IL7-Fc is principally beneficial for enhancing the efficacy of tumor-reactive T-cells in lymphopenic conditions for the ACT.