Details

Autor(en) / Beteiligte

• N’Guessan, Kombo F.
• Davis, Harold W.
• Chu, Zhengtao
• Vallabhapurapu, Subrahmanya D.
• Lewis, Clayton S.
• Franco, Robert S.
• Olowokure, Olugbenga
• Ahmad, Syed A.
• Yeh, Jen Jen
• Bogdanov, Vladimir Y.
• Qi, Xiaoyang

Titel

Enhanced Efficacy of Combination of Gemcitabine and Phosphatidylserine-Targeted Nanovesicles against Pancreatic Cancer

Ist Teil von

• Molecular therapy, 2020-08, Vol.28 (8), p.1876-1886

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Phosphatidylserine (PS) is often externalized in viable pancreatic cancer cells and is therapeutically targetable using PS-selective drugs. One of the first-line treatments for advanced pancreatic cancer disease, gemcitabine (GEM), provides only marginal benefit to patients. We therefore investigated the therapeutic benefits of combining GEM and the PS-targeting drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), for treating pancreatic ductal adenocarcinoma (PDAC). Using cell-cycle analyses and a cell surface PS-based sorting method in vitro, we observed an increase in surface PS as cells progress through the cell cycle from G1 to G2/M. We also observed that GEM treatment preferentially targets G1 phase cells that have low surface PS, resulting in an increased median surface PS level of PDAC cells. Inversely, SapC-DOPS preferentially targets high surface PS cells that are predominantly in the G2/M phase. Finally, combination therapy in subcutaneous and orthotopic PDAC tumors in vivo with SapC-DOPS and GEM or Abraxane (Abr)/GEM (one of the current standards of care) significantly inhibits tumor growth and increases survival compared with individual treatments. Our studies confirm a surface PS and cell cycle-based enhancement of cancer cytotoxicity following SapC-DOPS treatment in combination with GEM or Abr/GEM. Thus, PDAC patients treated with Abr/GEM may benefit from concurrent administration of SapC-DOPS. [Display omitted] SapC-DOPS nanovesicles, combined with standard care, gemcitabine/Abraxane, significantly inhibits pancreatic tumor growth and increases the survival of pancreatic tumor-bearing mice compared with either drug alone. Results of the study suggest that a phosphatidylserine and a cell-cycle-targeted mechanism regulate the enhanced therapeutic efficacy of the combination treatment.