Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation-induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma.
Original language | English (US) |
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Pages (from-to) | 2093-2100 |
Number of pages | 8 |
Journal | Molecular Pharmaceutics |
Volume | 12 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2015 |
Keywords
- DNA damage repair
- cyclopamine
- pancreatic cancer
- radiation sensitization
- stroma disruption
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery