Fucoidan Upregulates TLR4/CHOP-mediated Caspase-3 and PARP Activation to Enhance Cisplatin-induced Cytotoxicity in Human Lung Cancer Cells

Cisplatin-based therapy is a traditional, clinical treatment for cancers, including lung cancer. In this study, we found that sequential therapy, i.e., cisplatin followed by fucoidan, reduced tumor volume in an LLC1-bearing C57BL/6 mouse model. Using a series of combined therapeutic experiments, we found that the inhibition rate of the sequential treatment (cisplatin→fucoidan) was 50-75%. However, the inhibition rate of the sequential treatment, with fucoidan pretreatment, was increased to 75-85%. Moreover, we found that the simultaneous administration of fucoidan and cisplatin synergistically inhibited lung cancer cell viability via inducing apoptotic responses, including upregulating cleaved caspase-3 and poly (ADP ribose) polymerase (PARP) expression. Mechanistically, we demonstrated that the fucoidan-induced, TLR4-mediated endoplasmic reticulum stress molecule CHOP promoted caspase-3 activation, which was further stimulated by the cisplatin-induced DNA damage responses, and CHOP shRNA eliminated fucoidan-induced caspase-3 cleavage but did not affect cisplatin-mediated apoptotic molecules. In addition, we observed an increasing number of clinical results that suggest combined cisplatin and fucoidan exerts a greater anti-tumorigenic effect in patients with lung cancer in Taiwan. Together, our current results support the potential of combined fucoidan and cisplatin treatment as an effective therapeutic strategy in lung cancer.