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Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca 2+ -permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC 50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC 50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Tilorone is an interferon inducer with anticancer activity. Twenty-two novel tilorone analogs were synthesized by improvements of fluorenone skeleton, side chains and amino groups to screen new anticancer agents. In vitro evaluation showed that ten new compounds had better anticancer activities than tilorone. Among them, 2c (IC50 < 7 μM against cancer cell lines and IC50 > 35 μM against non-cancer cell lines) and 5d (IC50 < 10 μM against cancer cell lines and IC50 > 53 μM against non-cancer cell lines) exhibited the best anticancer activities and selectivities. Pharmacophore modeling of highly active compounds was carried out by Molecular Operating Environment (MOE) to generate a visualized model for compound design in future study., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A series of new 16β-azolyl-3β-amino-5α-androstane derivatives were synthesized and characterized. The new compounds were screened for their anticancer activity against the human cancer cell lines SW480, A549, HepG2, HeLa and SiHa in vitro using the MTT assay. The results of the in vitro study showed that a number of compounds have shown IC(50) values lower than 20 μM against the five cancer cell lines., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A series of new 16E-arylidene androstane derivatives were synthesized and characterized. The new compounds were screened for their anticancer activities against the human cancer cell lines SW480, A549, HepG2 and HeLa in vitro using the MTT assay. The results of the in vitro study showed that a number of compounds have shown IC(50) values lower than 20 μM against the four cancer cell lines., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Abstract: Earlier reports suggest that protoapigenone showed remarkable anticancer activities. In the present study, the cytotoxic effect of a new flavonoid, 2-(cis-1, 2-dihydroxy 4-oxo-cyclohex-5-enyl)-5, 7-dihydroxy-chromone (DEDC), which is a protoapigenone analog, was investigated in human hepatoma HepG2 cells. We found that hepatoma cells were highly susceptible to DEDC in contrast with normal cells. The sustainable and rapid generation of reactive oxygen species was observed in DEDC-induced cell death. Following oxidative stress, DEDC sequentially decreased mitochondrial membrane potential (ΔΨm), reduced Bcl-2 expression, increased cytochrome c release, and activated caspase-3, -8, and -9. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK) was stimulated by treatment with DEDC. To further investigate the mechanisms of the DEDC-induced cell death, we examined the effects of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) and selective inhibitors for MAPK pathways on the cell death. The DEDC-induced cell death was significantly inhibited by both NAC and JNK inhibitor SP600125, but promoted by p38 MAPK inhibitor, SB203580. Together, DEDC may have antitumor effects in HepG2 cells through reactive oxygen species production as well as activation of MAPK signaling pathways. [Copyright &y& Elsevier]

Nanocarriers hold great promise for the controlled release of therapeutic payloads to target organs/tissues and extended duration of anticancer agents in the bloodstream. However, limited data on their in vivo pharmacokinetics and delivery process hamper clinical applications. Here we report a series of micellar nanocarriers self-assembled from new-generation thiophenthiadiazole (TTD)-based NIR-II fluorophores HLAnP (n = 1–4) for simultaneous bioimaging and drug delivery. The NIR-II HLA4P nanocarrier displays exceptional non-fouling performance, minimal immunogenicity, ultralong blood half-life, and high tumor accumulation even with different administration routes. When used as a drug carrier, HLA4P with encapsulated doxorubicin (DOX) realized accurate tumor targeting and continuous real-time in vivo NIR-II tracking of drug delivery and therapy, showing a sustained release rate, improved therapeutic effect, and diminished cardiotoxicity as compared to free DOX. This study provides a new perspective on the design of dual-functional NIR-II fluorophores for diagnostic and therapeutic applications. An ultralow fouling NIR-II probe HLA4P self-assembled into micelles with long-circulation persistence and ultrahigh signal-background ratio for routine preoperative tumor assessment and trackable drug delivery. [Display omitted] • A new TTD-based NIR-II dye (HLA4P) with a high fluorescence QY, exceptional nonfouling performance and low immunogenicity. • HLA4P exhibited ultralong blood circulation, super-contrast ratio and long tumor retention by various injection routes. • HLA4P could be simultaneously used for long-term in vivo NIR-II tracking of drug delivery and therapy. • HLA4P@DOX showed sustained DOX release behavior, enhanced therapeutic effect and diminished toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Multifunctional and water-soluble superparamagnetic iron oxide (SPIO) nanocarriers were developed for targeted drug delivery and positron emission tomography/magnetic resonance imaging (PET/MRI) dual-modality imaging of tumors with integrin αvβ3 expression. An anticancer drug was conjugated onto the PEGylated SPIO nanocarriers via pH-sensitive bonds. Tumor-targeting ligands, cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) peptides, and PET 64Cu chelators, macrocyclic 1,4,7-triazacyclononane-N, N′, N″-triacetic acid (NOTA), were conjugated onto the distal ends of the PEG arms. The effectiveness of the SPIO nanocarriers as an MRI contrast agent was evaluated via an in vitro r2 MRI relaxivity measurement. cRGD-conjugated SPIO nanocarriers exhibited a higher level of cellular uptake than cRGD-free ones in vitro. Moreover, cRGD-conjugated SPIO nanocarriers showed a much higher level of tumor accumulation than cRGD-free ones according to non-invasive and quantitative PET imaging, and ex vivo biodistribution studies. Thus, these SPIO nanocarriers demonstrated promising properties for combined targeted anticancer drug delivery and PET/MRI dual-modality imaging of tumors. [Copyright &y& Elsevier]