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Tumor Biology

, Volume 36, Issue 6, pp 4213–4221 | Cite as

Bypassing the need for pre-sensitization of cancer cells for anticancer TRAIL therapy with secretion of novel cell penetrable form of Smac from hA-MSCs as cellular delivery vehicle

  • Mohsen Khorashadizadeh
  • Masoud Soleimani
  • Hossein Khanahmad
  • Ali Fallah
  • Mahmood Naderi
  • Mohammadreza Khorramizadeh
Research Article

Abstract

TNF-related apoptosis inducing ligand (TRAIL) is a novel anticancer agent with selective apoptosis-inducing activity on cancer cells. However, many malignant tumors still remain unresponsive. Although cells can bypass apoptosis by different functions, the defect in the blocking role of second mitochondria-derived activator of caspase (Smac) on X-linked inhibitor of apoptosis protein (XIAP) is known to be an important hub for immortal characteristic of malignant cells. Actually, XIAP is known as an apoptosis inhibitor. To date, the sensitization of cancerous cells to TRAIL was successfully performed with different protocols, mainly through blocking XIAP with Smac administration. However, all these sensitization methodologies need to be performed prior to TRAIL administration on cancerous cells which in turn limit their practical application in clinics. Therefore, we hypothesized that concurrent expression of Smac and TRAIL on human adipose-derived mesenchymal stem cells (hA-MSC-ST) could both sensitize and destroy cancerous cells. To this aim, we generated hA-MSC-ST, secreting a novel cell penetrable form of Smac and a trimeric form of TRAIL. Indeed, the cell penetrable form of Smac obviates the need for any pretreatment of cancerous cells. Our data depicted that individual overexpression of TRAIL or Smac in different breast cancer cell types induced limited or no apoptosis, respectively. Conversely, their concomitant overexpression markedly increased cell death even for a resistant type of breast cancer cells, MCF-7. Notably, we observed no cytotoxicity of our methodology on normal cells. In summary, this is the first demonstration that a dual approach using simultaneous overexpression of a cell penetrable form of Smac and TRAIL sensitize and promote apoptotic process even in resistant breast cancer cells.

Keywords

Mesenchymal stem cells TRAIL Smac XIAP Breast cancer 

Notes

Acknowledgments

This work was funded by the Tehran University of Medical Sciences, Tehran, Iran. The authors appreciate Stem Cell Technology Research Center, Tehran, Iran, for providing technical support. The authors are grateful to Mr. Majid Mosahebi for providing human fibroblast cells. Moreover, I would like to specially thank Dr. Haghpanah for his scientific comments during the writing of this manuscript.

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Mohsen Khorashadizadeh
    • 1
  • Masoud Soleimani
    • 2
  • Hossein Khanahmad
    • 3
  • Ali Fallah
    • 4
  • Mahmood Naderi
    • 5
    • 6
  • Mohammadreza Khorramizadeh
    • 1
    • 7
  1. 1.Department of Medical Biotechnology, School of Advanced Medical TechnologiesTehran University of Medical SciencesTehranIran
  2. 2.Department of HematologyTarbiat Modares UniversityTehranIran
  3. 3.Department of Genetics and Molecular Biology, Faculty of MedicineIsfahan University of Medical SciencesIsfahanIran
  4. 4.Systems and Synthetic Biology GroupMede Bioeconomy CompanyTehranIran
  5. 5.Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research InstituteTehran University of Medical SciencesTehranIran
  6. 6.Department of Molecular Biology and Genetic EngineeringStem Cell Technology Research CenterTehranIran
  7. 7.Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences InstituteTehran University of Medical SciencesTehranIran

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