Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery.

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors, and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression. Herein, we demonstrated that salvianic acid A (SAA) played a pivotal role in contributing to vascular normalization in the tumor-bearing mice, thereby improving delivery and effectiveness of the chemotherapeutic agent. SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells (HUVECs) exposed to hypoxia.

NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages.

Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings.

The role of glutamate receptors in the regulation of the tumor microenvironment.

Glutamate, as one of the most important carbon sources in the TCA cycle, is central in metabolic processes that will subsequently influence tumor progression. Several factors can affect the expression of glutamate receptors, playing either a tumor-promoting or tumor-suppressor role in cancer. Thus, the activation of glutamate receptors by the ligand could play a role in tumor development as ample studies have demonstrated the expression of glutamate receptors in a broad range of tumor cells.

The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation.

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases.

Control of Metastases via Myeloid CD39 and NK Cell Effector Function.

Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior antimetastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.

MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I-related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in mice, compared with wild-type mice.

Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23.

The glutamate metabotropic receptor 4 () locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that gene-targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12.

Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome.

Adjuvant immunotherapies targeting CTLA4 or PD-1 recently demonstrated efficacy in the treatment of earlier stages of human cancer. We previously demonstrated using mouse spontaneous metastasis models that neoadjuvant immunotherapy and surgery was superior, compared to surgery and adjuvant immunotherapy, in eradicating the lethal metastatic disease. However, the optimal scheduling between neoadjuvant immunotherapy and surgery and how it impacts on efficacy and development of immune-related adverse events (irAEs) remains undefined.

B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells.

Cancer stem cells (CSCs) have been implicated in metastasis, relapse, and therapeutic resistance of cancer, so successful cancer therapy may therefore require the development of drugs against CSCs or combining anti-CSCs drugs with conventional therapies. The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently activated signaling pathways in human cancer, playing a central role in tumorigenesis as well as the maintenance of CSCs. Here, we designed and identified B591, a dihydrobenzofuran-imidazolium salt, as a novel specific pan-PI3K inhibitor with potent inhibitory activity against class I PI3K isoforms, which showed effective inhibition of cellular PI3K/mTOR signaling pathway and robust antitumor activity in a set of cancer cell lines.

Experimental Lung Metastases in Mice Are More Effectively Inhibited by Blockade of IL23R than IL23.

Tumor-induced immunosuppression is mediated through various mechanisms including engagement of immune checkpoint receptors on effector cells, function of immunoregulatory cells such as regulatory T cells and myeloid-derived suppressor cells, and deployment of immunosuppressive cytokines such as TGFβ and IL10. IL23 is a cytokine that negatively affects antitumor immunity. In this study, we investigated whether IL23-deficient (IL23p19) and IL23R-deficient (IL23R) mice phenocopied each other, with respect to their tumor control.

Deficiency of host CD96 and PD-1 or TIGIT enhances tumor immunity without significantly compromising immune homeostasis.

Multiple non-redundant immunosuppressive pathways co-exist in the tumor microenvironment and their co-targeting can increase clinical responses. Indeed, concurrent blockade of CTLA-4 and PD-1 in patients with advanced melanoma increased clinical responses over monotherapy alone although the frequency and severity of immune related adverse events (irAEs) also increased. Nevertheless, a substantial number of patients still display an innate resistance phenotype and are unresponsive to current approved immunotherapies even when utilized in combination.

Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer.

The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we discuss the role IL-12 and IL-23 plays in tumor biology from preclinical and clinical data. In particular, we discuss the mechanism by which IL-23 promotes tumor growth and metastases and how the IL-12/IL-23 axis of inflammation can be targeted for cancer therapy.

Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway.

Ciclopirox olamine (CPX), a fungicide, has been demonstrated as a potential anticancer agent. However, the underlying anticancer mechanism is not well understood. Here, we found that CPX induced autophagy in human rhabdomyosarcoma (Rh30 and RD) cells.

Scapiformolactones A-I: germacrane sesquiterpenoids with an unusual Δ3-15,6-lactone moiety from Salvia scapiformis.

Nine germacrane sesquiterpenoids with an unusual Δ(3)-15,6-lactone moiety, scapiformolactones A-I (1-9), and one known seco-germacrane sesquiterpenoid, 3,7,11-trimethyldodeca-l,6,9-triene-3,11-diol (10), were isolated from whole plants of Salvia scapiformis Hance. Their structures were elucidated by spectroscopic methods including HR-ESIMS, IR, UV, NMR, and CD, as well as by quantum mechanical calculations and chemical transformations. Structures of compounds 1-3 were also confirmed by single-crystal X-ray diffraction analysis.

Mangiferin and its aglycone, norathyriol, improve glucose metabolism by activation of AMP-activated protein kinase.

Context: Mangiferin has been reported to possess antidiabetic activities. Norathyriol, a xanthone aglycone, has the same structure as mangiferin, except for a C-glucosyl bond. To our best knowledge, no study has been conducted to determine and compare those two compounds on glucose consumption in vitro.

Cytotoxic indole alkaloids from Tabernaemontana divaricata.

Five new vobasinyl-ibogan-type bisindole alkaloids, tabernaricatines A-E (1-5), two new monomers, tabernaricatines F and G (6 and 7), and 24 known indole alkaloids were isolated from the aerial parts of Tabernaemontana divaricata. Alkaloids 1 and 2 are the first vobasinyl-ibogan-type alkaloids possessing a six-membered ring via an ether linkage between C-17 and C-21. All compounds except for 3 were evaluated for their cytotoxicity against five human cancer cell lines; conophylline showed significant bioactivity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cells with IC₅₀ values of 0.

Trichothecin induces cell death in NF-κB constitutively activated human cancer cells via inhibition of IKKβ phosphorylation.

Constitutive activation of the transcription factor nuclear factor-κB (NF-κB) is involved in tumorigenesis and chemo-resistance. As the key regulator of NF-κB, IKKβ is a major therapeutic target for various cancers. Trichothecin (TCN) is a metabolite isolated from an endophytic fungus of the herbal plant Maytenus hookeri Loes.

Identification of two novel inhibitors of mTOR signaling pathway based on high content screening.

Purpose: Mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation and survival. Dysregulation of mTOR signaling pathway is closely involved in cancer development and chemotherapy resistance. Inhibitors of mTOR signaling pathway have been demonstrated to be attractive therapeutics for cancer therapy.

Synthesis and antitumor activities of novel dibenzo[b,d]furan-imidazole hybrid compounds.

A series of novel hybrid compounds between dibenzo[b,d]furan and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzimidazole ring, and the substitution of the imidazolyl-3-position with a naphthylacyl or 4-methoxyphenacyl group, were vital for modulating cytotoxic activity. In particular, hybrid compound 60 was found to be the most potent derivatives against all of human tumor cell lines investigated, while compound 49 was found to be more selective against breast carcinoma (MCF-7) and myeloid liver carcinoma (SMMC-7721).