Cyclopamine-Loaded Core-Cross-Linked Polymeric Micelles Enhance Radiation Response in Pancreatic Cancer and Pancreatic Stellate Cells

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; therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-crosslinked 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 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 radio-sensitization 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.

Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy

“…Because SHH inhibitors used at high doses might have caused significant systemic toxicity and possible off-target effects, we argued that the benefits of SHH inhibition in PDAC treatment should not be completely ruled out [13]. Numerous preclinical studies had shown that treatment with SHH inhibitors, e.g., cyclopamine (CPA) and IPA-926 (saridegib, a semisynthetic derivative of CPA), could increase tumor vasculature [14], sensitize tumor cells to radiotherapy [15], and deplete cancer stem cells [16].…”

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

“…Many studies have demonstrated that overexpression of Hh signaling genes is linked to radiation resistance, and downregulation can enhance radiation responses in many tumor types including pancreatic, anaplastic thyroid, esophageal, and non-small cell lung cancers [11-14]. In addition, several clinical studies have shown a positive correlation between overexpression of Hh signaling genes and poorer outcomes of various kinds of cancer [15-17].…”

Natural products remodel cancer-associated fibroblasts in desmoplastic tumors

“…To enhance the response of PDAC to ionizing radiation (IR), Zhao et al. 55 combined CPA-loaded core-crosslinked polymeric micelles (M-CPA) with Cs-137 radiation to enhance the radiation cytotoxicity of Cs-137. In their results, M-CPA treatment can decrease the number of CAFs, intimating that M-CPA may disrupt the tumor-associated stroma in vivo , thus relieving the hypoxia condition within the tumor microenvironment.…”