Fucoidan upregulates TLR4/CHOP-mediated caspase-3 and PARP activation to enhance cisplatin-induced cytotoxicity in human lung cancer cells

Cancer Lett. 2018 Sep 28:432:112-120. doi: 10.1016/j.canlet.2018.05.006. Epub 2018 May 8.

Abstract

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.

Keywords: Apoptosis; Combination index (CI); Fucoidan; Lung cancer; Synergistic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism*
  • Cell Cycle
  • Cell Proliferation
  • Cisplatin / administration & dosage
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Polysaccharides / administration & dosage
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • Tumor Cells, Cultured

Substances

  • DDIT3 protein, human
  • Polysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Transcription Factor CHOP
  • fucoidan
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • CASP3 protein, human
  • Caspase 3
  • Cisplatin