HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy

Abstract

As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer.

Y‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo

“…The cell cycle distribution was measured by propidium iodide staining, a typical method for cell cycle analysis since the 1970s . Briefly, cells were fixed with ice‐cold 70% ethanol overnight and stained with 50 μg/mL propidium iodide and 50 μg/mL RNase A .…”

“…The cell cycle distribution was measured by propidium iodide staining, a typical method for cell cycle analysis since the 1970s. (14)(15)(16)(17)(18)(19) Briefly, cells were fixed with ice-cold 70% ethanol overnight and stained with 50 lg ⁄ mL propidium iodide and 50 lg ⁄ mL RNase A. (20) The cell cycle was then measured by using a FACScan flow cytometer (BD Biosciences, San Jose, CA, USA) and analyzed with CellQuest Pro (BD Biosciences) and ModFit LT 3.0 software (Verity Software House).…”

A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding

“…The aberrant regulation of kinase enzymes is associated with virtually all major disease areas and are therefore regarded as important drug targets . Despite the advantages of fluorescence imaging in live cells, there are only a handful of examples in which fluorescent kinase inhibitors have been employed as a tool to study kinase inhibition in a cellular setting, while even fewer have been utilised for in vivo imaging studies …”

Investigation of Three Diasteromeric Chalcone Epoxides Derivatives by NMR Spectroscopy and X-ray Crystallography

“…In addition, it has also been shown that chalcone suppresses the activity of cyclooxygenase-2 and 5-lipoxygenase [10]. A number of recent studies have indicated that the antiinflammatory effect of chalcones is due to the inhibition of the NF-j B pathway, mediated by Ij-B degradation and the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun [8,11]. Chalcone oxides are commonly synthesized in plants and possess a potentially selected mechanism to inhibit the epoxide hydrolase enzyme from cellular cytosol [12].…”