Hybrid Benzoxazole-Coumarin Compounds Induce Death Receptor-Mediated Switchable Apoptotic and Necroptotic Cell Death on HN-5 Head and Neck Cancer Cell Line

Abstract

All three compounds were revealed IC50 value around 51.96±7.15 microM in HN-5 cells which were significantly lower than observed IC50 for AGO1522, 121.93±3.66 microM (p=0.001). Significant increase expression of FAS, FASL and TRIAL were observed in the treated cells with or without pretreatment with zVAD. In the absence of pretreatment, treatment lead to the induction of apoptosis with a significant increase in caspase-3 gene expression and caspase-3 activity without a significant increase in expression or activity of caspase-9 and other components of the intrinsic apoptotic pathway. However, in the zVAD pretreated cells, necroptotic cell death with a significant increase in expression of RIP1, RIP3, and MLKL genes was observed Conclusion: The novel hybrid benzoxazole-coumarins effectively induce Caspase-3 dependent apoptosis in HN-5 cancer cells, but also could circumvent the blockage of apoptotic cell death by induction of necroptosis.

Necroptosis in head and neck squamous cell carcinoma: characterization of clinicopathological relevance and in vitro cell model

“…In addition, under the same concentration of TNFα and Smac mimetic, the proportion of cell death in TSZ group was significantly higher than that in TS group, which is similar to the findings on other cancer cell lines 34,35,44 , suggesting that some tumor cells with apoptotic resistance may be more sensitive to necroptosis. Several researchers have already adopted this concept and proved that targeting necroptosis is a plausible method that can bypass the apoptotic resistance and kill tumor cells [45][46][47][48][49][50][51] . Moreover, it was also reported to induce antitumor immunity in tumor microenvironment because of the release of pro-inflammatory DAMPs 21,22,52,53 .…”

Design, Synthesis, and Evaluation of a New Series of Hydrazones as Small-Molecule Akt Inhibitors for NSCLC Therapy

“…Benzoxazoles are privileged building blocks for the synthesis of biologically active ligands targeting a plethora of crucial targets/pathways due to their unique features allowing them to effectively bind to diverse biological targets with distinct affinities. − Several studies have revealed that benzoxazoles exert marked cytotoxic activity against a variety of cancer cell lines through diverse mechanisms including induction of apoptosis, inhibition of Akt phosphorylation, and so on. − …”

“…The publications related to hydrazones − and benzoxazoles − exerting pronounced anticancer activity through inhibition of target enzymes involved in the pathogenesis of lung cancer motivated us to design novel anti-NSCLC agents by means of the molecular hybridization of the benzoxazole core with the hydrazide group, which was conjugated with the benzylidene moiety substituted at the para position with dialkylamino groups (dimethylamino, diethylamino), nitrogen-containing electron-withdrawing groups (nitro substituent), five- (pyrrolidine) or six-membered heterocyclic motifs (piperidine, morpholine and piperazine), heteroaromatic rings (imidazole, triazole) based on our previous work (Figure ), and the structure–activity relationships of existing Akt inhibitors together with the bioisosteric replacement. In this context, the designed compounds were synthesized readily and assessed for their cytotoxic properties on human lung adenocarcinoma (A549) and mouse embryonic fibroblast (L929) cells.…”

A new series of benzoxazole‐based SIRT1 modulators for targeted therapy of non‐small‐cell lung cancer

“…Due to their important features, benzoxazole derivatives are suitable candidates for targeted therapy of cancer. [ 16‐25 ] Besides, benzimidazole is a hot topic of research in pharmaceutical industry as a privileged scaffold due to its diverse therapeutic applications associated with its ability to bind with a variety of enzymes and receptors via proper interactions such as hydrogen bonds, ion–dipole, cation–π, π–π stacking, hydrophobic effect, the van der Waals force, and so on. [ 26‐36 ] Benzimidazole is a structural isostere of indole and purine nuclei, and this core is also an integral part of the structure of vitamin B 12 .…”