Title:Hybrid Benzoxazole-Coumarin Compounds Induce Death Receptor-Mediated Switchable Apoptotic and Necroptotic Cell Death on HN-5 Head and Neck Cancer Cell Line
Volume: 17
Issue: 4
Author(s): Sahar Yaghmaei, Parichehr Ghalayani, Siamak Salami*, Farahnaz Nourmohammadian, Soheila Koohestanimobarhan and Vahideh Imeni
Affiliation:
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran,Iran
Keywords:
Hybrid benzoxazole-coumarin, head and Neck cancer, HN-5 cell line, apoptosis, necroptosis.
Abstract: Background: Efficacy of multimodality approaches for the treatment of squamous cell cancer of the head
and neck has remained unsatisfactory and further advances are critically required. Targeted cell death induction is a
novel therapeutic approach that may help to improve clinical management of Head and Neck cancer patients.
Objective: The potency of novel hybrid benzoxazole-coumarins on the induction of apoptotic and/or necroptotic cell
death were evaluated in a Head and Neck carcinoma cell line, HN-5, and a human skin cell line, AGO1522.
Methods: Quantitative toxicity of the synthesized compounds were elucidated by MTT assay, the specific activity of
caspase-3 and -9 were measured by the colorimetric method and zVAD was used to block apoptosis. Expression of cell
death related genes were studied using quantitative PCR.
Results: 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.
