oxadiazoles and Neoplasm-Metastasis

This first-in-human, phase 1 study aimed to characterize the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, an oral selective androgen receptor (AR) modulator (SARM).. This dose-escalation study with a 3 + 3 design and PK expansion cohort enrolled postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were used as surrogate markers of AR engagement.. RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; ErbB Receptors; Female; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Nitriles; Oxadiazoles

Targeting the metastatic process to prevent disease dissemination in cancer remains challenging. One step in the metastatic cascade involves cancer cells transiting through the vascular endothelium after inflammation has increased the permeability of this cellular layer. Reducing inflammation-mediated gaps in the vascular endothelium could potentially be used to retard metastasis. This study describes the development of a novel ASR396-containing nanoparticle designed to activate the Sphingosine-1-Phosphate Receptor 1 (S1PR1) in order to tighten the junctions between the endothelial cells lining the vascular endothelium thereby inhibiting metastasis. ASR396 was derived from the S1PR1 agonist SEW2871 through chemical modification enabling the new compound to be loaded into a nanoliposome. ASR396 retained S1PR1 binding activity and the nanoliposomal formulation (nanoASR396) made it systemically bioavailable upon intravenous injection. Studies conducted in microvessels demonstrated that nanoASR396 significantly attenuated inflammatory mediator-induced permeability increase through the S1PR1 activation. Similarly, nanoASR396 inhibited gap formation mediated by inflammatory agents on an endothelial cell monolayer by decreasing levels of phosphorylated myosin light chain protein thereby inhibiting cellular contractility. In animal models, nanoASR396 inhibited lung metastasis by up to 80%, indicating its potential for retarding melanoma metastasis. Thus, a novel bioavailable nanoparticle-based S1PR1 agonist has been developed to negate the effects of inflammatory mediators on the vascular endothelium in order to reduce the metastatic dissemination of cancer cells.

Topics: Animals; Capillary Permeability; Cell Line, Tumor; Endothelial Cells; Humans; Liposomes; Mice; Myosin Light Chains; Nanoparticles; Neoplasm Metastasis; Oxadiazoles; Phosphorylation; Signal Transduction; Sphingosine-1-Phosphate Receptors; Thiophenes

A series of novel 18βH-glycyrrhetinic acid (GA) derivatives containing 3'-(alkyl/phenyl/pyridin(-2″, -3″, and -4″)-yl)-1',2',4'-oxadiazole moieties at the C-30 position were synthesized by condensation of triterpenoid's carboxyl group with corresponding amidoximes and further cyclization. Screening of the cytotoxicity of novel GA derivatives on a panel of tumor cell lines showed that the 3-acetoxy triterpenoid intermediates-

Topics: Acylation; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Carrageenan; Caspases; Cell Death; Cell Proliferation; Glycyrrhetinic Acid; HeLa Cells; Humans; Inflammation; Melanoma, Experimental; Mitochondria; Neoplasm Metastasis; Oxadiazoles; Oximes

Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT(1D) receptor (5-HT(1D)R) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT(1D)R-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT(1D)R antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT(1D)R played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT(1D)R in pulmonary metastasis of colorectal cancer.

Topics: Animals; Axin Protein; beta Catenin; Blotting, Western; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 7; Mice, Nude; Middle Aged; Neoplasm Metastasis; Oxadiazoles; Piperazines; Receptor, Serotonin, 5-HT1D; Reverse Transcriptase Polymerase Chain Reaction; Serotonin Antagonists; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

To investigate the inhibitory effect of a new compound of GLB on tumor metastasis in vivo and analyze its actions on tumor cell adhesion to clarify its mechanism.. The effect of GLB on tumor metastasis was analyzed by Lewis lung carcinoma model. The pathological morphology of lung alveolar was evaluated by hematoxylin-eosin staining. The effect of GLB on the proliferation of human prostate cancer cell (PC-3M, with a high metastatic characteristic) was studied using the MTT method, and its actions on PC-3M cell adhesion to human umbilical vein endothelial cells (HUVEC) and laminin were analyzed in vitro.. GLB (100 mg/kg/d for 28 d, ig) reduced the number of lung colonies of Lewis lung carcinoma metastasis significantly (P<0.05). Simultaneously, GLB could mitigate the damage of lung alveolar caused by metastasic tumor deposits. In vitro, GLB inhibited dramatically the adhesion of PC-3M cells to HUVEC (P< 0.01) and laminin (P<0.05), without cytotoxic or anti-proliferative action on PC-3M cells.. GLB has anti-tumor metastatic activity, which partly depends on its inhibition of tumor adhesion.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Female; Humans; Laminin; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Neoplasm Metastasis; Neoplasm Transplantation; Oxadiazoles; Prostatic Neoplasms; Pyrans; Spiro Compounds; Umbilical Veins