Combination therapy with c-met inhibitor and TRAIL enhances apoptosis in dedifferentiated liposarcoma patient-derived cells

BMC Cancer. 2019 May 24;19(1):496. doi: 10.1186/s12885-019-5713-2.

Abstract

Background: Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. Therefore, the development of advanced treatment strategies for LPS is required. In the present study, we investigated the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor on cell viability and apoptosis in LPS and DDLPS cell lines of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor.

Methods: We analyzed cell viability after treatment with TRAIL and a c-Met inhibitor by measuring CCK8 and death receptor 5 (DR5) expression levels via fluorescence activated cell sorting (FACS) in both sarcoma cell lines and DDLPS patient-derived cells (PDCs). Moreover, we validated the effects of TRAIL alone and in combination with c-Met inhibitor on apoptosis in LPS cell lines and DDLPS PDCs via FACS.

Results: Our results revealed that combination treatment with a c-Met inhibitor and human recombinant TRAIL (rhTRAIL) suppressed cell viability and induced cell death in both sarcoma cell lines and DDLPS PDCs, which showed varying sensitivities to rhTRAIL alone. Also, we confirmed that treatment with a c-Met inhibitor upregulated DR5 levels in sarcoma cell lines and DDLPS PDCs. In both TRAIL-susceptible and TRAIL-resistant cells subjected to combination treatment, promotion of apoptosis was dependent on DR5 upregulation.

Conclusion: From these results, our findings validated that DR5 up-regulation caused by combination therapy with a c-Met inhibitor and rhTRAIL enhanced TRAIL sensitization and promoted apoptosis. We propose the use of this approach to overcome TRAIL resistance and serve as a novel treatment strategy for clinical trials.

Keywords: C-met inhibitor; C-met receptor; Combination treatment; DR5; DR5 dependent apoptosis; Human recombinant TRAIL; Liposarcoma.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crizotinib / pharmacology*
  • Crizotinib / therapeutic use*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Drug Therapy, Combination
  • Flow Cytometry
  • Humans
  • Liposarcoma / drug therapy*
  • Liposarcoma / pathology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Recombinant Proteins / therapeutic use*
  • TNF-Related Apoptosis-Inducing Ligand / therapeutic use*

Substances

  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Crizotinib
  • Proto-Oncogene Proteins c-met